Intermediates useful for the preparation of antihistaminic piperidine derivatives

ABSTRACT

The present invention is related to a novel intermediates and processes which are useful in the preparation of certain antihistaminic piperidine derivatives of the formulawhereinW represents -C(=O)- or -CH(OH)-;R1 represents hydrogen or hydroxy;R2 represents hydrogen;R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;n is an integer of from 1 to 5;m is an integer 0 or 1;R3 is -COOH or -COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched each of A is hydrogen or hydroxy; andpharmaceutically acceptable salts and individual optical isomers thereof,with the proviso that where R1 and R2 are taken to form a second bond between the carbon atoms R1 and R2 or where R1 represented hydroxy integer 0.

This is a division of application Ser. No. 08/275,685, filed Jul. 14,1994, U.S. Pat. No. 6,242,606 now abandoned, which is acontinuation-in-part of application Ser. No. 08/237,466, filed May 11,1994,which is a continuation-in-part of application Ser. No. 08/144,084,filed Oct. 27, 1993, now abandoned, which is a continuation-in-part ofapplication Ser. No. 08/082,693, filed Jun. 25, 1993, now abandoned.

BACKGROUND OF THE INVENTION

The present invention is related to novel intermediates which are usefulin the preparation of certain piperidine derivatives which are useful asantihistamines, antiallergy agents and bronchodilators [U.S. Pat. No.4,254,129, Mar. 3, 1981, U.S. Pat. No. 4,254,130, Mar. 3, 1981, U.S.Pat. No. 4,285,958, Apr. 25, 1981 and U.S. Pat. No. 4,550,116, Oct. 29,1985].

These antihistaminic piperidine derivatives can be described by thefollowing formula:

wherein

W represents —C(═O)— or —CH(OH)—;

R₁ represents hydrogen or hydroxy;

R₂ represents hydrogen;

R₁ and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂;

n is an integer of from 1 to 5;

m is an integer 0 or 1;

R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbonatoms and is straight or branched;

each of A is hydrogen or hydroxy; and

pharmaceutically acceptable salts and individual optical isomersthereof,

with the proviso that where R₁ and R₂ are taken together to form asecond bond between the carbon atoms bearing R₁ and R₂ or where R₁represented hydroxy, m is an integer 0.

SUMMARY OF THE INVENTION

The present invention provides novel intermediates useful for thepreparation of certain antihistaminic piperidine derivatives of formula(I)

wherein

W represents —C(═O)— or —CH(OH)—;

R₁ represents hydrogen or hydroxy;

R₂ represents hydrogen; or

R₁ and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂;

n is an integer of from 1 to 5;

m is an integer 0 or 1;

R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbonatoms and is straight or branched;

each of A is hydrogen or hydroxy; and

pharmaceutically acceptable salts and individual optical isomersthereof,

with the proviso that where R₁ and R₂ are taken together to form asecond bond between the carbon atoms bearing R₁ and R₂ or where R₁represented hydroxy, m is an integer 0.

These novel intermediates are described by the following formulas:

wherein

A is a hydrogen or hydroxy; and

R₅ is H, —CH₂OD wherein D is hydrogen, acetate or benzoate, —CHO, Br,Cl, I, CN, —COOH, —COOalkyl or —CONR₆R₇ wherein the alkyl moiety hasfrom 1 to 6 carbon atoms and is straight or branched and R₆ and R₇ areeach independently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇ takentogether with the nitrogen atom form a pyrrolidine, piperidine ormorpholine, with the proviso that R₆ and R₇ cannot both be representedby C₁-C₆alkoxy.

wherein

A is a hydrogen or hydroxy; and

R₅ is H, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR₆R₇ wherein the alkylmoiety has from 1 to 6 carbon atoms and is straight or branched and R₆and R₇ are each independently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇taken together with the nitrogen atom form a pyrrolidine, piperidine ormorpholine, with the proviso that R₆ and R₇ cannot both be representedby C₁-C₆alkoxy.

wherein

A is a hydrogen or hydroxy; and

R₅ is H, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR₆R₇ wherein the alkylmoiety has from 1 to 6 carbon atoms and is straight or branched and R₆and R₇ are each independently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇taken together with the nitrogen atom form a pyrrolidine, piperidine ormorpholine, with the proviso that R₆ and R₇ cannot both be representedby C₁-C₆alkoxy.

wherein

Hal is Cl, Br or I;

n is an integer of from 1 to 5;

A is a hydrogen or hydroxy; and

R₅ is H, CH₂OD wherein D is hydrogen, acetate or benzoate, CHO, Br, Cl,I, CN, —COOH or —CONR₆R₇ wherein R₆ and R₇ are each independently H,C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇ taken together with the nitrogenatom form a pyrrolidine, piperidine or morpholine, with the proviso thatR₆ and R₇ cannot both be represented by C₁-C₆alkoxy.

wherein

Hal is Cl, Br or I;

n is an integer of from 1 to 5;

A is a hydrogen or hydroxy; and

R₅ is H, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR₆R₇ wherein the alkylmoiety has from 1 to 6 carbonatoms and is straight or branched and R₆and R₇ are each independently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇taken together with the nitrogen atom form a pyrrolidine, piperidine ormorpholine, with the proviso that R₆ and R₇ cannot both be representedby C₁-C₆alkoxy.

wherein

Hal is Cl, Br or I;

n is an integer of from 1 to 5;

A is a hydrogen or hydroxy;

R₅ is H, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR₆R₇ wherein the alkylmoiety has from 1 to 6 carbon atoms and is straight or branched and R₆and R₇ are each independently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇taken together with the nitrogen atom form a pyrrolidine, piperidine ormorpholine, with the proviso that R₆ and R₇ cannot both be representedby C₁-C₆alkoxy.

wherein

Hal is Cl, Br or I;

n is an integer of from 1 to 5; and

A is a hydrogen or hydroxy.

wherein A is a hydrogen or hydroxy.

wherein

Hal is Cl, Br or I;

n is an integer of from 1 to 5;

A is a hydrogen or hydroxy.; and

R₅ is H, CH₂OD wherein D is hydrogen, acetate or benzoate, CHO, Br, Cl,I, CN, —COOH, —COOalkyl or —CONR₆R₇ wherein the alkyl moiety has from 1to 6 carbon atoms and is straight or branched and R₆ and R₇ are eachindependently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇ taken togetherwith the nitrogen atom form a pyrrolidine, piperidine or morpholine,with the proviso that R₆ and R₇ cannot both be represented byC₁-C₆alkoxy; and

individual optical isomers thereof.

wherein

W represents —C(═O)— or —CE(OH)—;

R₁ represents hydrogen or hydroxy;

R₂ represents hydrogen; or

R₁ and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂;

n is an integer of from 1 to 5;

m is an integer 0 or 1;

R₅ is H, Br, Cl, I, CN or —CONR₆R₇ wherein R₆ and R₇ are eachindependently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇ taken togetherwith the nitrogen atom form a pyrrolidine, piperidine or morpholine,with the proviso that R₆ and R₇ cannot both be represented byC₁-C₆alkoxy;

A is hydrogen or hydroxy; and

pharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer 0.

In addition, the present invention provides novel processes forpreparing the antihistaminic piperidine derivatives of formula

wherein

W represents —C(═O)— or —CH(OH)—;

R₁ represents hydrogen or hydroxy;

R₂ represents hydrogen; or

R₁ and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂;

n is an integer of from 1 to 5;

m is an integer 0 or 1;

R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbonatoms and is straight or branched;

each of A is hydrogen or hydroxy; and

pharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer 0, comprising the steps of:

(a) reacting a cumene compound of the formula

wherein A is as defined above with a ω-halo compound of the formula

wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is asdefined above, in the presence of a suitable Lewis acid to produce aω-halo cumylketone compound;

(b) reacting the ω-halo cumylketone compound with a suitablehalogenating agent to give a ω-halo-halocumylketone compound;

(c) reacting the ω-halo-halocumylketone compound compound with asuitable cyanating agent to give a ω-halo-cyanocumylketone compound;

(d) reacting the ω-halo-cyanocumylketone compound with an appropriatestraight or branched C₁-C₆ alcohol in the presence of a suitableanhydrous acid to give a ω′-halo-α′-keto-α,α-dimethylphenylacetic acidimidate compound;

(e) reacting the ω-halo-α′-keto-α,αdimethylphenylacetic acid imidatecompound with water to give a ω′-halo-α′-keto-α,α-dimethylphenylaceticacid ester compound;

(f) reacting the ω-halo-α′-keto-α,α-dimethylphenylacetic acid estercompound with a piperidine compound of the formula

wherein R₁, R₂ and m are as defined above in the presence of a suitablenon-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W is —C(═O)—;

(g) optionally hydrolyzing the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is COOalkyl and W is —C(═O)— toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is COOH and W is —C(═O)—;

(h) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is COOalkyl and W is —C(═O)— or theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)—; and

(i) optionally reacting the ω′-piperidine-α′-hydroxy-α,α-dimethylphenylderivative of formula (I) wherein R₃ is —COOH and W is —CH(OH)— or theappropriate ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —C(═O)— with an appropriatestraight or branched C₁-C₆ alcohol in the presence of a suitable acid toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is -COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative wherein R₃ is—COOalkyl and W is —C(═O)—; and

(j) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— with an appropriatedeprotecting reagent,

with the proviso that each of the hydroxy groups present in thecompounds described in steps a-i are optionally protected orunprotected.

In addition, the present invention provides novel processes forpreparing the antihistaminic piperidine derivatives of formula

wherein

W represents —C(═O)— or —CH(OH)—;

R₁ represents hydrogen or hydroxy;

R₂ represents hydrogen; or

R₁ and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂;

n is an integer of from 1 to 5;

m is an integer 0 or 1;

R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbonatoms and is straight or branched;

each of A is hydrogen or hydroxy; and

pharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer 0, comprising the steps of:

(a) reacting a ω-halo-halocumylketone compound with carbon dioxide underelectrochemical reduction conditions to give aω′-halo-α′-keto-α,α-dimethylphenylacetic compound;

(b) reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic compoundcompound with an appropriate straight or branched C₁-C₆ alcohol in thepresence of a suitable anhydrous acid to give aω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound;

(c) reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid estercompound with a piperidine compound of the formula

wherein R₁, R₂ and m are as defined above in the presence of a suitablenon-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W=—C(═O)—;

(d) optionally hydrolyzing the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is

COOalkyl and W is —C(═O)— to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)—;

(e) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is COOalkyl and W is —C(═O)— or theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)—; and

(f) optionally reacting the ω′-piperidine-α′-hydroxy-α,α-dimethylphenylderivative of formula (I) wherein R₃ is —COOH and W is —CH(OH)— or theappropriate ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —C(═O)— with an appropriatestraight or branched C₁-C₆ alcohol in the presence of a suitable acid toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is -COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; and

(g) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α′,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— with an appropriatedeprotecting reagent,

with the proviso that each of the hydroxy groups present in thecompounds described in steps a-f are optionally protected orunprotected.

In addition, the present invention provides novel processes forpreparing the antihistaminic piperidine derivatives of formula

wherein

W represents —C(═O)— or —CH(OH)—;

R₁ represents hydrogen or hydroxy;

R₂ represents hydrogen; or

R₁ and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂;

n is an integer 3;

m is an integer 0 or 1;

R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbonatoms and is straight or branched;

each of A is hydrogen or hydroxy; and

pharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer 0, comprising the steps of:

(a) reacting a cumyl compound of the formula

wherein A is as defined above with an appropriate cyclopropyl compoundof the structure

wherein B is halo or hydroxy, in the presence of a suitable Lewis acidto produce a cyclopropyl cumylketone compound;

(b) reacting the cyclopropyl cumylketone compound with a suitablehalogenating agent to give a cyclopropyl halocumylketone compound;

(c) reacting the cyclopropyl halocumylketone compound with carbondioxide under electrochemical reduction conditions to give acyclopropylketo-α,α-dimethylphenylacetic acid compound;

(d) reacting the cyclopropylketo-α,α-dimethylphenylacetic with anappropriate straight or branched C₁-C₆ alcohol in the presence of asuitable anhydrous acid to give aω′-halo-α-keto-α,α-dimethylphenylacetic acid ester compound;

(e) reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid estercompound with a piperidine compound of the formula

wherein R₁, R₂ and m are as defined above in the presence of a suitablenon-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W=—C(═O)—;

(f) optionally hydrolyzing the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is COOalkyl and W is —C(═O)— toproduce a ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula(I) wherein R₃ is COOH and W is —C(═O)—;

(g) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is COOalkyl and W is —C(═O)— or theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)—; and

(h) optionally reacting the ω′-piperidine-α′-hydroxy-α,α-dimethylphenylderivative of formula (I) wherein R₃ is —COOH and W is —CH(OH)— or theappropriate ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —C(═O)— with an appropriatestraight or branched C₁-C₆ alcohol in the presence of a suitable acid toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O); and

(i) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— with an appropriatedeprotecting reagent,

with the proviso that each of the hydroxy groups present in thecompounds described in steps a-h are optionally protected orunprotected.

Another embodiment of the present invention involves a process forpreparing the piperidine derivatives of formula

wherein

W represents —C(═O)— or —CH(OH)—;

R₁ represents hydrogen or hydroxy;

R₂ represents hydrogen; or

R₁ and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂;

n is an integer of from 1 to 5;

m is an integer 0 or 1;

R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbonatoms and is straight or branched;

each of A is hydrogen or hydroxy; and

pharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer 0, comprising the steps of:

(a) reacting a α,α-dimethylphenylacetic acid amide compound of theformula

wherein A is as defined above and R₆ and R₇ are each independently H,C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇ taken together with the nitrogenatom for a pyrrolidine, piperidine or morpholine, with the proviso thatR₆ and R₇ cannot both be represented by C₁-C₆alkoxy with a ω-halocompound of the formula

wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is asdefined above, in the presence of a suitable Lewis acid to produce aω′-halo-α′-keto-α,α-dimethylphenylacetic acid amide compound;

(b) reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid amidecompound with a piperidine compound of the formula

wherein R₁ and R₂ are as defined above in the presence of a suitablenon-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (XI)wherein R₅ is —CONR₆R₇ wherein R₆ and R₇ are as defined above;

(c) optionally hydrolyzing the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (XI) wherein R₅ is —CONR₆R₇ wherein R₆ and R₇ areas defined above to produce a ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is COOH and W is —C(═O)—;

(d) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is COOH and W is —C(═O)— with asuitable reducing agent to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)—; and

(e) optionally reacting the ω′-piperidine-α′-hydroxy-α,α-dimethylphenylderivative of formula (I) wherein R₃ is —COOH and W is —CH(OH)— or theappropriate ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —C(═O)— with an appropriatestraight or branched C₁-C₆ alcohol in the presence of a suitable acid toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R3 is —COOalkyl and W is —C(═O)—; and

(f) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— with an appropriatedeprotecting reagent,

with the proviso that each of the hydroxy groups present in thecompounds described in steps a-e are optionally protected orunprotected.

Another embodiment of the present invention involves a process forpreparing the piperidine derivatives of formula

wherein

W represents —C(═O)— or —CH(OH)—;

R₁ represents hydrogen or hydroxy;

R₂ represents hydrogen; or

R₁ and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂;

n is an integer of from 1 to 5;

m is an integer 0 or 1;

R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbonatoms and is straight or branched;

each of A is hydrogen or hydroxy; and

pharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer 0, comprising the steps of:

(a) reacting a toluene compound of the formula

wherein A is as defined above with a ω-halo compound of the formula

wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is asdefined above, in the presence of a suitable Lewis acid to produce aω-halo-tolylketone compound;

(b) reacting the ω-halo-tolylketone compound with a suitable base togive a cyclopropyl-tolylketone compound;

(c) reacting the cyclopropyl-tolylketone compound with a suitablehalogenating agent to give a cyclopropyl-halotolylketone compound;

(d) reacting the cyclopropyl-halotolylketone compound with a suitablecyanating agent to give a cyclopropyl cyanotolylketone compound;

(e) reacting the cyclopropyl cyanotolylketone compound with a suitablemethylating agent to give a cyclopropyl cyanocumylketone compound;

(f) reacting the cyclopropyl cyanocumylketone compound with a suitablebase to give a cyclopropylketo-α,α-dimethylphenylacetic acid amide;

(g) reacting the cyclopropylketo-α,α-dimethylphenylacetic acid amidewith an appropriate straight or branched C₁-C₆ alcohol in the presenceof a suitable anhydrous acid to give aω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound;

(h) reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid estercompound with a piperidine compound of the formula

wherein R₁, R₂ and m are as defined above in the presence of a suitablenon-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative;

(i) optionally hydrolyzing the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative to produce a ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is COOH and W is —C(═O)—;

(j) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is COOH and W is —C(═O)— with asuitable reducing agent to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)—; and

(k) optionally reacting the ω′-piperidine-α′-hydroxy-α,α-dimethylphenylderivative of formula (I) wherein R₃ is —COOH and W is —CH(OH)— or theappropriate ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —C(═O)— with an appropriatestraight or branched C₁-C₆ alcohol in the presence of a suitable acid toproduce a ω′-piperidine-al-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (II)wherein R₃ is —COOalkyl and W is —C(═O)—; and

(l) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (II) wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (II)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl of formula (I) wherein R₃ is—COOalkyl and W is —CH(OH)— with an appropriate deprotecting reagent,

with the proviso that each of the hydroxy groups present in thecompounds described in steps a-k are optionally protected orunprotected.

Another embodiment of the present invention involves a process forpreparing the piperidine derivatives of formula

wherein

W represents —C(═O)— or —CH(OH)—;

R₁ represents hydrogen or hydroxy;

R₂ represents hydrogen; or

R₁ and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂;

n is an integer of from 1 to 5;

m is an integer 0 or 1;

R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbonatoms and is straight or branched;

each of A is hydrogen or hydroxy; and

pharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer 0, comprising the steps of:

(a) reacting a phenylacetic acid ester compound of the formula

wherein A is as defined above with a ω-halo compound of the formula

wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is asdefined above, in the presence of a suitable Lewis acid to produce aω′-halo-α′-keto-phenylacetic acid ester compound;

(b) reacting the ω′-halo-α′-keto-phenylacetic acid ester compound with asuitable methylating agent in the presence of a suitable base to give acyclopropylketo-α,α-dimethylphenylacetic acid ester;

(c) purifying the cyclopropylketo-α,α-dimethylphenylacetic acid ester bydistillation and/or recrystallization;

(d) reacting the cyclopropylketo-α,α-dimethylphenylacetic acid esterwith an appropriate straight or branched C₁-C₆ alcohol in the presenceof a suitable anhydrous acid to give aω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound;

(e) reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid estercompound with a piperidine compound of the formula

wherein R₁, R₂ and m are as defined above in the presence of a suitablenon-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—;

(f) optionally hydrolyzing the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is —COOalkyl and W is —C(═O)— toproduce a ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula(I) wherein R₃ is COOH and W is —C(═O)—;

(g) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is COOH and W is —C(═O)— with asuitable reducing agent to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)—; and

(h) optionally reacting the ω′-piperidine-α′-hydroxy-α,α-dimethylphenylderivative of formula (I) wherein R₃ is —COOH and W is —CH(OH)— or theappropriate ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —C(═O)— with an appropriatestraight or branched C₁-C₆ alcohol in the presence of a suitable acid toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is -COOalkyl ad W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; and

(i) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl of formula (I) wherein R₃ is-COOalkyl and W is —CH(OH)— with an appropriate deprotecting reagent,

with the proviso that each of the hydroxy groups present in thecompounds described in steps a-h are optionally protected orunprotected.

(g) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is COOH and W is —C(═O)— with asuitable reducing agent to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)—; and

(h) optionally reacting the ω′-piperidine-α′-hydroxy-α,α-dimethylphenylderivative of formula (I) wherein R₃ is —COOH and W is —CH(OH)— or theappropriate ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —C(═O)— with an appropriatestraight or branched C₁-C₆ alcohol in the presence of a suitable acid toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; and

(i) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative-of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl of formula (I) wherein R₃ is—COOalkyl and W is —CH(OH)— with an appropriate deprotecting reagent,with the proviso that each of the hydroxy groups present in thecompounds described in steps a-h are optionally protected orunprotected.

As used herein, the term “C₁-C₆alkyl” or “alkyl” refers to a straight orbranched alkyl group having from 1 to 6 carbon atoms and as referred toherein are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, n-pentyl, neopentyl and n-hexyl. The term “C₁-C₆alkoxy”refers to a straight or branched alkoxy group having from 1 to 6 carbonatoms and as referred to herein are methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy andn-hexoxy. The term “Hal” or “halo” refers to a halogen group andincludes Cl, Br or I.

The piperidine derivatives of the formula (IX) can form pharmaceuticallyacceptable salts. Pharmaceutically acceptable acid addition salts of thecompounds of this invention are those of any suitable inorganic ororganic acid. Suitable inorganic acids are, for example, hydrochloric,hydrobromic, sulfuric, and phosphoric acids. Suitable organic acidsinclude carboxylic acids, such as, acetic, propionic, glycolic, lactic,pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamic,ascorbic, maleic, hydroxymaleic, and dihydroxymaleic, benzoic,phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranillic, cinnamic,salicyclic, 4-aminosalicyclic, 2-phenoxybenzoic, 2-acetoxybenzoic, andmandelic acid, sulfonic acids, such as, methanesulfonic, ethanesulfonicand B-hydroxyethanesulfonic acid. Non-toxic salts of the compounds ofthe above-identified formula formed with inorganic or organic bases arealso included within the scope of this invention and include, forexample, those of alkali metals, such as, sodium, potassium and lithium,alkaline earth metals, for example, calcium and magnesium, light metalsof group IIIA, for example, aluminum, organic amines, such as, primary,secondary or tertiary amines, for example, cyclohexylamine, ethylamine,pyridine, methylaminoethanol and piperazine. The salts are prepared byconventional means as, for example, by treating a piperidine derivativeof formula (I) with an appropriate acid or base.

The novel intermediates of formula (II), formula (III), formula (IV),formula (V), formula (VI) and formula (VII) wherein R₅ is hydrogen maybe prepared as described in Scheme A. In Scheme A, all substituents areas previously defined unless otherwise indicated.

Scheme A provides various general synthetic procedures for preparing thenovel intermediates of formula (II), formula (III) and formula (IV)wherein R₅ is hydrogen.

In step a, the appropriate toluene derivative of structure (1) ismethylated to give the corresponding ethylbenzene derivative ofstructure (2).

For example, the appropriate toluene derivative of structure (1) isreacted with a slight molar excess of an appropriate methylating agent,such as iodomethane, chloromethane or bromomethane in the presence of asuitable non-nucleophilic base, such as potassium t-butoxide or sodiumhydride. The reaction is typically conducted in a suitable organicsolvent, such as diglyme, tert-butyl methyl ether or methylene chloride,for a period of time ranging from 30 minutes to 24 hours and at atemperature range of from −78° C. to room temperature. The correspondingethylbenzene derivative of structure (2) is recovered from the reactionzone by extractive methods as is known in the art and may be purified bydistillation.

In step b, the appropriate ethylbenzene derivative of structure (2) ismethylated to give the corresponding cumene derivative of structure (3)as described previously in step a, but using at least 2 molarequivalents of methylating agent.

In step c, the appropriate toluene derivative of structure (1) isdimethylated to give the corresponding cumeme derivative of structure(3) as described previously in step a but using at least 2 molarequivalents of methylating agent.

In step d, the appropriate toluene derivative of structure (1) isacylated with an appropriate ω-halo compound of the structureHal-(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined to give the corresponding ω-halotolylketone compound of structure (4).

For example, the appropriate ω-halo tolylketone compound of structure(4) may be prepared by reacting an appropriate toluene derivative ofstructure (1) with an appropriate ω-halo compound of the structureHal-(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined, which are known in the art or areprepared by procedures well known in the art, under the generalconditions of a Friedel-Crafts acylation using a suitable Lewis acid.The reaction is carried out in a solvent, such as carbon disulfide,1,2-dichloroethane, n-hexane, acetonitrile, 1-nitropropane,nitromethane, diethyl ether and carbon tetrachloride, methylenechloride, tetrachloroethane or nitrobenzene with methylene chloridebeing the preferred solvent. The reaction time varies from about ½ hourto 25 hours, preferably 10 to 16 hours and the reaction temperaturevaries from about 0° C. to 25° C. The corresponding ω-halo tolylketonecompound of structure (4) is recovered from the reaction none by anaqueous quench followed by extraction as is known in the art. The ω-halotolylketone compound of structure (4) may be purified by procedures wellknown in the art, such as crystallization and/or distillation.

Alternatively, the appropriate toluene derivative of structure (1) maybe acylated with the S-halo compound of the structureHal-(CH₂)_(n)—C(═O)—B, wherein B is hydroxy, Hal is Cl, Br or I and n isas previously defined in the presence of a Lewis acid to give thecorresponding ω-halo tolylketone compound of structure (4) as describedin Arch. Pharm. 306, 807 1973. In general, an appropriate toluenederivative of structure (1) and the ω-halo compound of the structureHal-(CH₂)_(n)—C(═O)—B, wherein B is hydroxy, are melted together atabout 50° C., then cooled to about 10° C. after which a Lewis acid isadded in an amount about 2.2 times the molar amount of the appropriatetoluene derivative of structure (1) employed. The mixture is heated atabout 70° C. for about 2 hours after which a 30% sodium acetate solutionis added and extracted with ether.

The organic layer is dried and the solvent evaporated to give thecorresponding ω-halo tolylketone compound of structure (4). The ω-halotolylketone compound of structure (4) may be purified by procedures wellknown in the art, such as crystallization and/or distillation.

Suitable Lewis acids for the acylation reaction described in step d arewell known and appreciated in the art. Examples of suitable Lewis acidsare boron trichloride, aluminum chloride, titanium tetrachloride, borontrifluoride, tin tetrachloride, ferric chloride, cobalt(II) chloride andzinc chloride, with aluminum chloride being preferred. The selection andutilization of suitable Lewis acids for the acylation reaction of step dis well known and appreciated by one of ordinary skill in the art.

The starting ω-halo compound of the structure Hal-(CH₂)_(n)—C(═O)—B,wherein B is Hal or hydroxy, Hal is Cl, Br or I and n is as previouslydefined are commercially available of easily prepared by generally knownmethods.

While also not necessary for utilization in the acylation reaction ofstep d, the phenol functionality of those toluene derivatives ofstructure (1), wherein A is hydroxy may be protected with a suitableprotecting group. For example, suitable protecting groups for thephenolic hydroxy include methyl ether, 2-methoxyethoxymethyl ether(MEM), cyclohexyl ether, o-nitrobenzyl ether, 9-anthryl ether,t-butyldimethylsilyl ether, acetate, benzoate, methyl carbamate, benzylcarbamate, aryl pivaloate and aryl methanesulfonate.

In step e, to appropriate toluene derivative of structure (1) isacylated with an appropriate cyclopropyl compound of the structure

wherein B is as previously defined to give the corresponding cyclopropyltolylketone derivative of structure (5) as described previously in stepd.

In step f, the appropriate ethylbenzene derivative of structure (2) isacylated with an appropriate ω-halo compound of the structureHal-(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined to give the corresponding ω-haloethylphenylketone compound of structure (6) as described previously instep d.

In step g, the appropriate ethylbenzene derivative of structure (2) isacylated with an appropriate cyclopropyl compound of the structure

wherein B is as previously defined to give the corresponding cyclopropylethylphenylketone derivative of structure (7) as described previously instep e.

In step h, the appropriate cumene derivative of structure (3) isacylated with an appropriate ω-halo compound of the structureHal-(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined to give the corresponding ω-halocumylketone compound of structure (8) as described previously in step d.

In step i, to appropriate cumene derivative of structure (3) is acylatedwith an appropriate cyclopropyl compound of the structure

wherein B is as previously defined to give the corresponding cyclopropylcumylketone derivative of structure (9) as described previously in stepe.

In step j, the cyclopropyl functionality of the appropriate cyclopropyltolylketone derivative of structure (5) is ring-opened to give thecorresponding ω-halo tolylketone compound of structure (4) wherein n=3.

For example, the appropriate cyclopropyl tolylketone derivative ofstructure (5) is reacted with an appropriate hydrogen halide in asuitable organic solvent, such as toluene, xylene and ethanol. Thereaction is typically conducted at a temperature range of from roomtemperature to 70° C. and for a period of time ranging from 20 minutesto 10 hours. The corresponding ω-halo tolylketone compound of structure(4) wherein n=3 is isolated from the reaction zone by evaporation of thesolvent or may be stored in a solution of the hydrogen halide.

In step k, the appropriate ω-halo tolylketone compound of structure (4)wherein n=3 is ring-closed to give the corresponding cyclopropyltolylketone derivative of structure (5).

For example, the appropriate ω-halo tolylketone compound of structure(4) wherein n=3 is reacted with an appropriate non-nucleophilic base,such as sodium hydroxide or potassium hydroxide in a suitable organicprotic solvent, such as methanol or ethanol. The reaction is typicallyconducted at a temperature range of from −10° C. to room temperature andfor a period of time ranging from 10 minutes to 5 hours. Thecorresponding cyclopropyl tolylketone derivative of structure (5) isisolated from the reaction zone by extractive methods as are known inthe art and may be purified by distillation.

In step 1, the cyclopropyl functionality of the appropriate cyclopropylethylphenylketone derivative of structure (7) is ring-opened to give thecorresponding ω-halo ethylphenylketone compound of structure (6) whereinn=3 as described-previously in step j.

In step m, the appropriate ω-halo ethylphenylketone compound ofstructure (6) wherein n=3 is ring-closed to give the correspondingcyclopropyl ethylphenylketone derivative of structure (7) as describedpreviously in step k.

In step n, the cyclopropyl functionality of the appropriate cyclopropylcumylketone derivative of structure (9) is ring-opened to give thecorresponding ω-halo cumylketone compound of structure (8) wherein n=3as described previously in step j.

In step o, the appropriate ω-halo cumylketone compound of structure (8)wherein n=3 is ring-closed to give the corresponding cyclopropylcumylketone derivative of structure (9) as described previously in stepk.

In step p, the appropriate ω-halo ethylphenylketone compound ofstructure (6) is methylated to give the corresponding ω-halo cumylketonecompound of structure (8) as described previously in step a.

In step q, the appropriate cyclopropyl tolylkeFtone derivative ofstructure (5) is dimethylated to give the corresponding cyclopropylcumylketone derivative of structure (9) as described previously in stepc.

In step r, the appropriate ω-halo tolylketone compound of structure (4)is methylated to give the corresponding ω-halo ethylphenylketonecompound of Structure (6) as described previously in step a.

In step s, the appropriate ω-halo tolylketone compound of structure (4)is dimethylated to give the corresponding ω-halo cumylketone compound ofstructure (8) as described previously in step c.

In step t, the appropriate cyclopropyl ethylphenylketone derivative ofstructure (7) is methylated to give the corresponding cyclopropylcumylketone derivative of structure (9) as described previously in stepa.

In step u, the appropriate cyclopropyl tolylketone derivative ofstructure (5) is methylated to give the corresponding cyclopropylethylphenylketone derivative of structure (7) as described previously instep a.

Starting materials for use in Scheme A are readily available to one ofordinary skill in the art.

The following examples present typical syntheses as described in SchemeA. These examples are understood to be illustrative only and are notintended to limit the scope of the present invention in any way. As usedherein, the following terms have the indicated meanings: “g” refers tograms; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 1

Step h: 4-Chloro-1-(4-isopropyl-phenyl)-butan-1-one

Slurry aluminum chloride (140.9 g, 1.075 mol) and 4-chlorobutyrylchloride (148 g, 1.05 mol) in methylene chloride (1.0 L) add, bydropwise addition, cumene (125 g, 1.04 mol) over a thirty minute periodunder a nitrogen atmosphere while maintaining the internal temperaturebetween 5-8° C. with an ice bath. Allow the stirred solution to come toroom temperature and continue stirring under nitrogen for 14 hours.Cautiously add the methylene chloride solution to 1 L of crushed icewith stirring and add additional methylene chloride (400 mL). Separatethe organic phase and wash with 10% hydrochloric acid (3×300 mL), water(3×300 mL), 10% sodium bicarbonate (3×300 mL) and water (3×300 mL). Dry(MgSO₄), filter and wash with methylene chloride (150 mL). Evaporate thesolvent to give the title compound (203 g, 86%) as a clear oil whichcrystallizes on standing; mp 35-37° C.

¹H NMR (300 MHz, CDCl₃) δ 7.91 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz,2H), 3.65 (t, J=6.3 Hz, 2H), 3.13 (t, J=6.9 Hz, 2H), 2.95 (p, J=6.9 Hz,1H), 2.20 (p, J=6.6 Hz, 2H), 1.26 (d, J=6.9 Hz, 6H); ¹³C NMR (75 MHz,CDCl₃) δ 198.2, 154.4, 134.4, 128.1, 126.5, 44.5, 32.96, 34.0, 26.7,23.5; IR (CDCl₃) 2950, 2920, 1675, 1680, 1600, 1410, 1225 cm⁻¹; MS(GCCIMS (methane)) 255 (3), 251 (10), 227 (30 (M+H)), 225 (100 (M+H)),189 (70), 147 (95), 107 (13, 105 (40).

Anal. Calcd for C₁₃H₁₇OCl: C, 69.48; H, 7.62; Found: C, 69.31; H, 7.39.

EXAMPLE 2

Step d: 4-Chloro-1-(4-methyl-phenyl)-butan-1-one

Suspend anhydrous AlCl₃ (156 g, 1.15 mol) in toluene (1500 mL) and coolto 2-4° C. Add, by slow addition, a solution of 4-chlorobutyryl chloride(165.5 g, 1.15 mol) in toluene (300 mL). Stir for 15 minutes and pourinto stirring ice-water (2.5 L). Stir for 30 hours, decant the tolueneand extract the aqueous phase with toluene (700 mL). Combine the organiclayers and wash three times with water (1 L, 1 L, 500 mL). Evaporate thesolvent in vacuo to give the title compound as a pale yellow oil (292.3g, 95%).

EXAMPLE 3

Step k: Cyclopropyl-p-tolyl-methanone

Dissolve potassium hydroxide (126 g) in methanol (450 mL), stir and coolin an ice-water bath. Add, by dropwise addition, a solution of4-chloro-1-(4-methyl-phenyl)-butan-1-one (292 g) in methanol (450 mL).Stir for 20 minutes at 8-10° C. and partially evaporate the methanol invacuo to give 400 mL of a residue. Pour the residue, with stirring, intowater (1500 mL), filter the white solid and dry under vacuum to give thetitle compound as a white solid (190.8 g, 90%).

The following compounds can be prepared using the methodology depictedin Scheme A:

Cyclopropyl-(4-isopropyl-phenyl)-methanone;

Cyclopropyl-(4-ethyl-phenyl)-methanone; and

4-Chloro-1-(4-ethyl-phenyl)-butan-1-one.

The novel intermediates of formula (II), formula (III), formula (IV),formula (V), formula (VI) and formula (VII) wherein R₅ is OH, Cl, Br orI may be prepared as described in Scheme B. In Scheme B, allsubstituents are as previously defined unless otherwise indicated.

Scheme B provides various general synthetic procedures for preparing thenovel intermediates of formula (II), formula (III), formula (IV),formula (V), formula (VI) and formula (VII) wherein R₅ is OH, Cl, Br orI.

In step a, the appropriate ω-halo cumylketone compound of structure (8)is halogenated to give the corresponding ω-halo-halocumylketone compoundof structure (10).

For example, the appropriate ω-halo-halocumylketone compound ofstructure (10) may be prepared by reacting an appropriate ω-halocumylketone compound of structure (8) with a suitable halogenating agentoptionally in the presence of a catalytic amount of a suitableinitiator. Examples of suitable brominating agents areN-bromosuccinimide, and 1,3-dibromo-5,5-dimethyl hydantoin, withN-bromosuccinimide being preferred. An example of suitable chlorinatingagent is N-chlorosuccinimide and an example of a suitable iodinatingagent is N-iodosuccinimide. Examples of suitable initiators are benzoylperoxide, AIBN, t-butyl peroxide and ultraviolet light. The reaction iscarried out in a solvent, such as carbon tetrachloride, methylenechloride, 1,2-dichlorobenzene, 1,2-dichloroethane, ethyl formate orethyl acetate, with carbon tetrachloride being the preferred solvent.The reaction time varies from about ½ hour to 8 hours, preferably ½ to 2hours and the reaction temperature varies from about 25° C. to thereflux temperature of the solvent employed, preferably 76° C. to 80° C.The corresponding ω-halo-halocumylketone compound of structure (10) isrecovered from the reaction zone by extractive methods as are known inthe art followed by evaporation of the solvent.

In addition, the halogenation reaction of step a may be carried out in a2-phase procedure. For example, the appropriate ω-halo-halocumylketonecompound of structure (10) may be prepared by reacting an appropriateω-halo cumylketone compound of structure (8) with a suitablehalogenating agent, such as sodium bromate/sodium bromide, in a solventmixture such as methylene chloride and water, catalyzing the reactionwith, for example, ultraviolet light. The correspondingω-halo-halocumylketone compound of structure (10) is recovered from thereaction zone by extractive methods as are known in the art followed byevaporation of the solvent.

The ω-halo-halocumylketone compound of structure (10) maydehydrohalogenate to the corresponding α-methylstyrene, giving variousmixtures of ω-halo-halocumylketone compound of structure (10) andα-methylstyrene compounds. The α-methylstyrene compounds in such amixture may be back-converted to ω-halo-halocumylketone compound ofstructure (10) by treatment with anhydrous hydrogen halide gas.Typically, a solution of the mixture of ω-halo-halocumylketone compoundof structure (10) and α-methylstyrene compounds-in a suitable organicsolvent, such as methylene chloride or acetonitrile, is treated with asuitable anhydrous hydrogen halide )as, such as hydrogen chloride. Thereaction is typically treated with the hydrogen halide gas for a periodof time ranging from 30 minutes to 5 hours and at a temperature range offrom 0° C. to room temperature. The remediated ω-halo-halocumylketonecompound of structure (10) may be isolated by evaporation of solvent,but may be stored as a solution in the organic solvent containinghydrogen halide gas.

In addition, halogen exchange of the benzylic halogen can beaccomplished by thorough solvolysis in the presence of the appropriatehydrogen halide.

For example, the ω-chloro-halocumylketone compound of structure (10) canbe prepared from the ω-bromo-halocumylketone compound of structure (10)by thorough aqueous solvolysis in the presence of hydrogen-chloride.

In step b, the appropriate cyclopropyl cumylketone derivative ofstructure (9) is halogenated to give the corresponding cyclopropylhalocumylketone compound of structure (11) as described previously instep a.

In step c, the cyclopropyl functionality of the appropriate cyclopropylhalocumylketone compound of structure (11) is ring-opened to give thecorresponding ω-halo-halocumylketone compound of structure (10) whereinn =3 as described previously in Scheme A, step j.

In step d, the appropriate ω-halo ethylphenylketone compound ofstructure (6) is halogenated to give the correspondingω-halo-haloethylphenylketone compound of structure (12) as describedpreviously in step a.

In step e, the appropriate ω-halo tolylketone compound of structure (4)is halogenated to give the corresponding ω-halo halotolylketone compoundof structure (13) as described previously in step a.

In step f, the appropriate cyclopropyl ethylphenylketone derivative ofstructure (7) is halogenated to give the corresponding cyclopropylhaloethylphenylketone compound of structure (14) as described previouslyin step a.

In step g, the appropriate cyclopropyl tolylketone derivative ofstructure (5) is halogenated to give the corresponding cyclopropylhalotolylketone of structure (15) as described previously in step a.

In step h, the appropriate cyclopropyl halotolylketone of structure (15)is ring-opened to give the corresponding ω-halo halotolylketone compoundof structure (13) wherein n=3 as described previously in Scheme A, stepj.

In step i, the appropriate cyclopropyl haloethylphenylketone compound ofstructure (14) is ring-opened to give the correspondingω-halo-haloethylphenylketone compound of structure (12) wherein n=3 asdescribed previously in Scheme A, step j.

In addition, the novel intermediates of formula (II), formula (III),formula (IV), formula (V), formula (VI) and formula (VII) wherein R₅ isOH may be prepared by solvolysis of the corresponding novelintermediates of formula (II), formula (III), formula (IV), formula (V),formula (VI) and formula (VII) wherein R₅ is Cl, Br or I, with,for-example, tetrahydrofuran and water or any slightly acidic medium.

Starting materials for use in Scheme B are readily available to one ofordinary skill in the art.

The following examples present typical syntheses as described in SchemeB. These examples are understood to be illustrative only and are notintended to limit the scope of the present invention in any way. As usedherein, the following terms have the indicated meanings: “g” refers tograms; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “IC” refers to degrees Celsius; “mm Hg” refersto millimeters of mercury; “μL” refers to microliters; “μg” refers tomicrograms; and “μM” refers to micromolar.

EXAMPLE 4 1-[4-(1-Bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one

Step a, Method A:

Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (2.10 g, 9.35 mmol)in carbontetrachloride (30 mL), add N-bromosuccinimide (1.75 g, 9.83mmol) and benzoylperoxide (3 mg) and stir at reflux for 1 hour. Cool thereaction mixture, filter, wash with water and brine. Dry (MgSO₄), filterand evaporate the solvent in vacuo to give the title compound as anamber oil.

Step a, Method B:

Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (5.00 g, 22.2 mmol)and N-bromosuccinimide (4.1 g, 23.0 mmol) in carbon tetrachloride (25mL) and add AIBN radical initiator (300 mg). Stir and maintain under anitrogen atmosphere at 80-90° C. or optionally irradiate with a sunlampuntil a vigorous exotherm occurs at which point momentarily remove untilreflux subsides and then reapply the heat. Reflux for 30 minutes and addanother potion of N-bromosuccinimide (100 mg) while maintaining refluxand reflux an additional 15 minutes. Cool to room temperature andprecipitate the succinimide from the solution by -allowing to standovernight. Filter and wash the succinimide (2.25 g) with carbontetrachloride (20 mL). Combine the filtrates and evaporate the solventin vacuo to give the title compound as a yellow oil (6.80 g, 100%).

1H NMR (300 MHz, CDCl₃) δ 7.935 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz,2H), 3.66 (t, J=6.3 Hz, 2H), 3.16 (t, J=6.8 Hz, 2H), 2.21 (p, J=6.8 Hz,2H), 2.19 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) 6198.1 (151.63), 135.8,128.0, 126.0, 62.3, 44.5, 35.3, 35.1, 26.7; IR (neat) 2970, 2910, 1680,1675, 1600, 1402, 1225, 1180 cm⁻¹.

Step a, Method C:

Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (74.7 g, 333 mmol)in methylene chloride (250 mL) and add sodium bromate (17.6 g, 117 mmol)in water (75 mL) in a three-necked Morton flask equipped with anoverhead stirrer. Cool the solution to 10° C. and irradiate with two 150W incandescent flood lamps. Add, by dropwise addition, a solution ofsodium bromide (24 g, 233 mmol) and stir for 2 hours. Illuminate foranother 30 minutes, add sodium dithionate (2.0 g), separate the organicphase, dry (MgSO₄) and evaporate the solvent in vacuo to give the titlecompound (100 g, 99%).

Step a, Method D:

Dissolve 1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one(10.4 g assayed at 67% by weight and containing 18wt %1-[4-(2-propene)-phenyl]-4-chloro-butan-1-one) in methylene chloride (50mL) and sparge hydrogen chloride through the solution for 70 minutes.Evaporate the solvent in vacuo to give a 3:1 mixture of1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one and1-[4-(1-chloro-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (11.6 g);

EXAMPLE 5

(4-Bromomethyl-phenyl)-cyclopropyl-methanone

Step g: Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (20 g, 124mmol) and 2,2′-Azolons (2-methylpropionitrile) (0.5 g) in methylenechloride (100 mL) and cool to 5° C. Add a suspension ofN-bromosuccinimide (12 g) in methylene chloride (50 mL) and irradiatewith light (150 Watt lamp), maintaining the temperature at 5° C. After2, 3 and 7 hour time periods, add additional N-bromosuccinimide (6 g, 6g, 2.8 g) and continue stirring. After 7.5 hours, wash with water (200mL) and with 0.4M sodium hydrogen carbonate (2×200 mL). Dry (Na₂SO₄),evaporate the solvent invacuo and recrystallize (hexane) to give thetitle compound as a crystalline solid (26.7 g).

The following compounds can be prepared by procedures depicted in SchemeB:

[4-(1-bromoethyl)-phenyl]-cyclopropyl-methanone;

[4-(1-bromo-1-methyl-ethyl)-phenyl]-cyclopropyl-methanone;

1-[4-(l-bromomethyl)-phenyl]-4-chloro-butan-1-one; and

1-[4-(1-bromoethyl)-phenyl]-4-chloro-butan-1-one.

The novel intermediates of formula (VIII) and (IX) and the novelintermediates of formula (II), formula (III), formula (IV), formula (V),formula (VI) and formula (VII) wherein R₅ is Cl, Br or I may also beprepared as described in Scheme C. In Scheme C, all substituents are aspreviously defined unless otherwise indicated.

Scheme C provides various general synthetic procedures for preparing thethe novel intermediates of formula (VIII) and (IX) and novelintermediates of formula (II), formula (III), formula (IV), formula (V),formula (VI) and formula (VII) wherein R₅ is Cl, Br or I.

In step a, the appropriate α-methylstyrene compound of structure (16) isacylated with an appropriate ω-halo compound of the structureHal-(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined to give the correspondingω-halo-α-methylstyrene compound of structure (17) as describedpreviously in Scheme A, step d.

In step b, the appropriate α-methylstyrene compound of structure (16) isacylated with an appropriate cyclopropyl compound of the structure

wherein B is as previously defined to give the corresponding cyclopropylα-methylstyreneketone derivative of structure (18) as describedpreviously in Scheme A, step e.

In step c, the appropriate ω-halo-α-methylstyrene compound of structure(17) wherein n=3 is ring-closed to give the corresponding cyclopropylα-methylstyreneketone derivative of structure (18) as describedpreviously in Scheme A, step k.

In step d, the appropriate cyclopropyl α-methylstyreneketone derivativeof structure (18) is ring-opened to give the correspondingω-halo-α-methylstyrene compound of structure (17) wherein n=3 asdescribed previously in Scheme A, step j.

In step e, the appropriate ω-halo-α-methylstyrene compound of structure(17) is hydrohalogenated to give the correspondingω-halo-halocumylketone derivative of structure (10).

For example, the appropriate ω-halo-α-methylstyrene compound ofstructure (17) is treated with anhydrous hydrogen halide at atemperature range of from −50° C. to room temperature, preferably 0° C.−5° C. and for a period of time ranging from 5 minutes to 2 hours. Theω-halo-halocurylketone derivative of structure (10) is recovered fromthe reaction zone by purging with nitrogen.

In step f, the appropriate ω-halo-halocumylketone derivative ofstructure (10) is dehydrohalogenated to give the correspondingω-halo-α-methylstyrene compound of structure (17) by treatment with baseas is known in the art.

In step g, the appropriate cyclopropyl α-methylstyreneketone derivativeof structure (18) is hydrohalogenated to give the correspondingcyclopropyl halocumylketone compound of structure (11) as describedpreviously in step e.

In step h, the appropriate cyclopropyl halocumylketone compound ofstructure (11) is dehydrohalogenated to give the correspondingcyclopropyl α-methylstyreneketone derivative of structure (18) asdescribed previously in step f.

The novel intermediates of formula (II), formula (III), formula (IV),formula (V), formula (VI) and formula (VII) wherein R₅ is CN may beprepared as described in Scheme D. In Scheme D, all substituents are aspreviously defined unless otherwise indicated.

Scheme D provides various general synthetic procedures for preparing thenovel intermediates of formula (II),

formula (III), formula (IV), formula (V), formula (VI) and formula (VII)wherein R₅ is CN.

In step a, the appropriate ω-halo-halocumylketone compound of structure(10) is cyanated to give the corresponding ω-halo-cyanocumylketonecompound of structure (19).

For example, the appropriate ω-halo-cyanocurylketone compound ofstructure (19) may be prepared by reacting an appropriateω-halo-halocumylketone compound of structure (10) with a suitablecyanating agent. Examples of suitable cyanating agents aretrimethylsilyl cyanide, diethylaluminum cyanide and tetrabutylammoniumcyanide, with trimethylsilyl cyanide being preferred. The reaction iscarried out in a solvent, such as methylene chloride, tetrachloroethaneand carbon tetrachloride, with methylene chloride being the preferredsolvent. A catalytic amount of a suitable Lewis acid may also beemployed in the reaction. Examples of suitable Lewis acids are borontrichloride, aluminum chloride, titanium tetrachloride, borontrifluoride, tin tetrachloride and zinc chloride, with tin tetrachloridebeing preferred. The reaction time varies from about ½ hour to 8 hours,preferably ½ to 2 hours and the reaction temperature varies from about0° C. to room temperature, preferably room temperature. Theω-halo-cyanocumylketone compound of structure (16) is recovered from thereaction zone by an aqueous quench followed by extraction as is known inthe art. The ω-halo-cyanocumylketone compound of structure (16) may bepurified by procedures well known in the art, such as chromatography andcrystallization.

In step b, the appropriate ω-halo cumylketone compound of structure (8)is cyanated to give the corresponding ω-halo-cyanocumylketone compoundof structure (19).

For example, the ω-halo-cyanocumylketone compound of structure (19) maybe prepared by reacting an appropriate the ω-halo cumylketone compoundof structure (8) with a suitable cyanating agent. Examples of suitablecyanating agent are cyanogen chloride, cyanogen bromide and cyanogeniodide, with cyanogen chloride being preferred. The reaction is carriedout according to the procedures outlined by Tanner and Bunce, J. Am.Chem. Soc., 91, 3028 (1969).

In step c, the appropriate cyclopropyl halocumylketone compound ofstructure (11) is cyanated to give the corresponding cyclopropylcyanocumylketone compound of structure (20) as described previously instep a.

In step d, the appropriate cyclopropyl cumylketone derivative ofstructure (9) is cyanated to give the corresponding cyclopropylcyanocumylketone compound of structure (20) as described previously instep b.

In step e, the appropriate ω-halo-haloethylphenylketone compound ofstructure (12) is cyanated to give the correspondingω-halo-cyanoethylphenylketone compound of structure (21) as describedpreviously in step a.

In step f, the appropriate ω-halo-ethylphenylketone compound ofstructure (6) is cyanated to give the correspondingω-halo-cyanoethylphenylketone compound of structure (21) as describedpreviously in step b.

In step g, the appropriate ω-halo halotolylketone compound of structure(13) is cyanated to give the corresponding ω-halo cyanotolylketonecompound of structure (22) as described previously in step a.

In step h, the appropriate ω-halo tolylketone compound of structure (4)is cyanated to give the corresponding ω-halo cyanotolylketone compoundof structure (22) as described previously in step b.

In step i, the appropriate cyclopropyl ethylphenylketone compound ofstructure (7) is cyanated to give the corresponding cyclopropylcyanoethylphenylketone compound of structure (23) as describedpreviously in step b.

In step j, the appropriate cyclopropyl haloethylphenylketone compound ofstructure (14) is cyanated to give the corresponding cyclopropylcyanoethylphenylketone compound of structure (23) as describedpreviously in step a.

In step k, the appropriate cyclopropyl tolylketone compound of structure(5) is cyanated to give the corresponding cyclopropyl cyanotolylketonecompound of structure (24) as described previously in step b.

In step l, the appropriate cyclopropyl halotolylketone of structure (15)is cyanated to give the corresponding cyclopropyl cyanotolylketonecompound of structure (24) as described previously in step a.

Starting materials for use in Scheme D are readily available to one ofordinary skill in the art.

The following examples present typical syntheses as described in SchemeD. These examples are understood to be illustrative only and are notintended to limit the scope of the present invention in any way. As usedherein, the following terms have the indicated meanings: “g” refers tograms; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 6

Step a: 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionitirile

Dissolve 1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chlorobutan-1-one (2.00g, 6.59 mmol) in anhydrous methylene chloride (20 mL) and place under-anargon atmosphere. Add trimethylsilyl cyanide (1.10 mL, 8.25 mmol)followed by tin (IV) chloride (0.20 mL, 1.7 mmol) via syringe. Stir atreflux for 1 hour, add water (20 mL) and stir for an additional ½ hour.Separate the layers and extract the aqueous layer with methylenechloride. Combine the organic layers, wash with brine, dry (MgSO4),filter and evaporate the solvent in vacuo. Purify by silica gelchromatography (15% ethyl acetate/hexane) to give the title compound asa white solid; mp 79-80° C.

EXAMPLE 7

Step l: (4-Cyclopropanecarbonyl-phenyl)-acetonitrile

Mix (4-bromomethyl-phenyl)-cyclopropyl-methanone (5.0 g, 21 mmol),potassium cyanide (2.0 g, 30 mmol), tetra-butylammonium bromide (150mg), water (5 mL) and acetonitrile (50 mL). Mechanically stir at roomtemperature for 3 hours, pour into water (450 mL) and stir overnight.Collect by filtration and recrystallize (hexane) to give the titlecompound as a white crystalline solid; mp 86-87° C.

The following compounds can be prepared by the-synthetic proceduresdepicted in Scheme D:

2-(4-Cyclopropanecarbonyl-phenyl)-propionitrile;

2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile;

[4-(4-Chloro-butyryl)-phenyl]-acetonitrile; and

2-[4-(4-Chloro-butyryl)-phenyl]-propionitrile.

The novel intermediates of formula (II), formula (III), formula (IV),formula (V), formula (VI) and formula (VII) wherein R₅ is CN may also beprepared as described in Scheme E. In Scheme E, all substituents are aspreviously defined unless otherwise indicated.

Scheme E provides alternative various general synthetic procedures forpreparing the novel intermediates of formula (II), formula (III),formula (IV), formula (V), formula (VI) and formula (VII) wherein R₅ isCN.

In step a, the appropriate phenylacetonitrile compound of structure (25)is methylated to give the corresponding 2-cyanoethylbenzene compound ofstructure (26) as described previously in Scheme A, step a.

Appropriate phenylacetonitrile compounds of structure (25) may beprepared from the corresponding benzyl halide by techniques andprocedures well known by one of ordinary skill in the art and describedpreviously in Scheme D, step a.

Appropriate benzyl halide compounds may be prepared from thecorresponding toluene derivative of structure (1) as describedpreviously in Scheme B, step a.

In step b, the appropriate 2-cyanoethylbenzene compound of structure(26) is methylated to give the corresponding 2-cyano-2-propylbenzenecompound of structure (27) as described previously in Scheme A, step a.

Appropriate 2-cyanoethylbenzene compound of structure (26) may beprepared from the corresponding α-methylbenzyl halide by techniques andprocedures well known by one of ordinary skill in the art and asdescribed previously in step a.

Appropriate α-methylbenzyl halide compounds may be prepared from thecorresponding ethylbenzene derivative of structure (2) as describedpreviously in Scheme B, step a.

In step c, the appropriate phenylacetonitrile compound of structure (25)is dimethylated to give the corresponding 2-cyano-2-propylbenzenecompound of structure (27) as described previously in Scheme A, step c.

In step d, the appropriate phenylacetonitrile compound of structure (25)is acylated with an appropriate ω-halo compound of the structureHal-(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined to give the corresponding ω-halocyanotolylketone compound of structure (22) as described previously inScheme A, step d.

In step e, the appropriate phenylacetonitrile compound of structure (25)is acylated with an appropriate cyclopropyl compound of the structure

wherein B is as previously defined to give the corresponding cyclopropylcyanotolylketone compound of structure (24) as described previously inScheme A, step e.

In step f, the appropriate 2-cyanoethylbenzene compound of structure(26) is acylated with an appropriate ω-halo compound of the structureHal-(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined to give the correspondingω-halo-cyanoethylphenylketone compound of structure (21) as describedpreviously in Scheme A, step d.

In step g, the appropriate 2-cyanoethylbenzene compound of structure(26) is acylated with an appropriate cyclopropyl compound of thestructure

wherein B is as previously defined to give the corresponding cyclopropylcyanoethylphenylketone compound of structure (23) as describedpreviously in Scheme A, step e.

In step h, the appropriate 2-cyano-2-propylbenzene compound of structure(27) is acylated with an appropriate ω-halo compound of the structureHal-(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined to give the correspondingω-halo-cyanocumylketone compound of structure (19) as describedpreviously in Scheme A, step d.

Appropriate 2-cyano-2-propylbenzene compound of structure (27) may beprepared from the corresponding α,α-dimethylbenzyl halide by techniquesand procedures well known by one of ordinary skill in the art and asdescribed previously in step a.

Appropriate α,α-dimethylbenzyl halide compounds may be prepared from thecorresponding cumene derivative of structure (3) as described previouslyin Scheme B, step a.

In step i, the appropriate 2-cyano-2-propylbenzene compound of structure(27) is acylated with an appropriate cyclopropyl compound of thestructure

wherein B is as previously defined to give the corresponding cyclopropylcyanocumylketone compound of structure (20) as described previously inScheme A, step e.

In step j, the cyclopropyl functionality of the appropriate cyclopropylcyanotolylketone compound of structure (24) is ring-opened to give thecorresponding ω-halo cyanotolylketone compound of structure (22) whereinn=3 as described previously in Scheme A, step j.

In step k, the appropriate ω-halo cyanotolylketone compound of structure(22) wherein n=3 is ring-closed to give the corresponding cyclopropylcyanotolylketone compound of structure (24) as described previously inScheme A, step k.

In step l, the cyclopropyl functionality of the appropriate cyclopropylcyanoethylphenylketone compound of structure (23) is ring-opened to givethe corresponding ω-halo-cyanoethylphenylketone compound of structure(21) wherein n=3 as described previously in Scheme A, step j.

In step m, the appropriate ω-halo-cyanoethylphenylketone compound ofstructure (21) wherein n=3 is ring-closed to give the correspondingcyclopropyl cyanoethylphenylketone compound of structure (23) asdescribed previously in Scheme A, step k.

In step n, the cyclopropyl functionality of-the appropriate cyclopropylcyanocumylketone compound of structure (20) is ring-opened to give thecorresponding ω-halo-cyanocumylketone compound of structure (19) whereinn=3 as described previously in Scheme A, step j.

In step o, the appropriate ω-halo-cyanocumylketone compound of structure(19) is ring-closed to give the corresponding cyclopropylcyanocumylketone compound of structure (20) as described previously inScheme A, step k.

In step p, the appropriate ω-halo-cyanoethylphenylketone compound ofstructure (21) is methylated to give the correspondingω-halo-cyanocumylketone compound of structure (19) as describedpreviously in Scheme A, step a.

In step q, the appropriate cyclopropyl cyanotolylketone compound ofstructure (24) is dimethylated to give the corresponding cyclopropylcyanocumylketone compound of structure (20) as described previously inScheme A, step c.

In step r, the appropriate ω-halo cyanotolylketone compound of structure(22) is methylated to give the correspondingω-halo-cyanoethylphenylketone compound of structure (21) as describedpreviously in Scheme A, step a.

In step s, the appropriate ω-halo cyanotolylketone compound of structure(22) is dimethylated to give the corresponding ω-halo-cyanocumylketonecompound of structure (19) as described previously in Scheme A, step c.

In step t, the appropriate cyclopropyl cyanoethylphenylketone compoundof structure (23) is methylated to give the corresponding cyclopropylcyanocumylketone compound of structure (20) as described previously inScheme A, step a.

In step u, the appropriate cyclopropyl cyanotolylketone compound ofstructure (24) is methylated to give the corresponding cyclopropylcyanoethylphenylketone compound of structure (23) as describedpreviously in Scheme A, step a.

Starting materials for use in Scheme E are readily available to one ofordinary skill in the art.

The following examples-present typical syntheses as described in SchemeE. These examples are understood to be illustrative only and are notintended to limit the scope of the present invention in any way. As usedherein, the following terms have the indicated meanings: “g” refers tograms; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 8

Step c: Cumyl cyanide

Place phenylacetonitrile (92.3 mL, 0.800 mol), tetra n-butylammoniumchloride (4.45 g of a 50% solution, 8.0 mmol) and 50% aqueous sodiumhydroxide solution (2.874 mole NaOH) into a 3-neck round-bottom flask,with a thermowell, overheard stirrer, reflux condenser with adry-ice/acetone trap and a sparge tube. Heat to 40-70 C with stirring at115 RPM (paddle stir blade), and bubble in methyl chloride gas (11.7 g,0.232 mole) over a 30 minute period. Turn off the methylchlorideaddition and heat and stir overnight.

Sparge additional methyl chloride (35.4 g, 0.700 mol) into the reactionmixture (heated to 35 C) over a period of 2 hours. Stir the resultingmixture at ambient temperature for 22 hours and sparge additional methylchloride (39.5 g, 0.781 mol) into the reaction mixture at a temperatureof 40-70 C (mostly at 55-60 C). Sparge additional methyl chloride (8.7g, 0.172 mol) into the reaction mixture and allow to cool to 30 C.Remove the condenser and add deionized water (250 mL) and heptane (250mL). Transfer to a separatory funnel and draw off the aqueous (bottom)layer. Wash the remining organic layer with fresh water (2×100 mL),evaporate the solvent in vacuo to give a dark red oil.

Add the oil, 50% aqueous sodium hydroxide (79 g, 0.988 mole) and tetran-butylammonium chloride (1.0 g, 3.6 mmol) to a 500 mL 3-necked roundbottom flask with a magnetic stir bar. Using the same experimentalprocedure described above, sparge in methyl chloride. Heat to 40-60 C,stir and sparge in methyl chloride (20.5 g, 0.40 mole) over 1 hour.Allow the reaction mixture to cool, add deionized water (100 g) andstir. Allow the layers to settle and remove the bottom layer by pipet.Repeat wash with additional water (100 g) to give the title compound asa dark orange oil (111.0 g, wet with water).

EXAMPLE 9

Step g: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile

Dissolve potassium t-butoxide (2.42 g, 21.6 mmol) in diglyme (8 mL),cool to 10° C. and slowly add with mechanical stirring, a solution of(4-cyclopropanecarbonyl-phenyl)-acetonitrile (2 g, 10.8 mmol) and methyliodide (1.5 mL, 24.0 mmol) in diglyme (10 mL). After 10 minutes, addadditional potassium t-butoxide (0.3 g, 2.6 mmol) in diglyme (2 mL) andstir for a total of 45 minutes. Pour into a mixture of water (100 mL)and ethyl acetate (50 mL) and adjust the pH to 1.5-2 withdilutebydrochloric acid. Separate the organic phase and extract theaqueous phase with ethyl acetate (50 mL). Combine the organic phases andwash with brine (2×100 mL). Dry (Na₂SO₄), evaporate the solvent in vacuoand recrystallize (ethyl ether/hexane) to give the title compound as ayellow solid; mp 80-82° C.

The following compounds can be prepared by procedures depicted in SchemeE:

(4-Cyclopropanecarbonyl-phenyl)-acetonitrile;

2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionitirile;

2-(4-Cyclopropanecarbonyl-phenyl)-propionitrile;

[4-(4-Chloro-butyryl)-phenyl]-acetonitrile; and

2-[4-(4-Chloro-butyryl)-phenyl]-propionitrile.

The novel intermediates of formula (II), formula (III), formula (IV),formula (V), formula (VI) and formula (VII) wherein R₅ is COOalkyl mayalso be prepared as described in Scheme F. In Scheme F, all substituentsare as previously defined unless otherwise indicated.

Scheme F provides alternative various general synthetic procedures forpreparing the novel intermediates of formula (II), formula (III),formula (IV), formula (V), formula (VI) and formula (VII) wherein R₅ isCOOalkyl.

In step a, the appropriate phenylacetic acid ester compound of structure(28) is methylated to give the corresponding α-methylphenylacetic acidester compound of structure (29) as described previously in Scheme A,step a.

Appropriate phenylacetic acid ester compounds of structure (28) areprepared from the corresponding phenylacetic acid compounds by standardesterification reactions which are well known by one of ordinary skillin the art.

Appropriate phenylacetic acid compounds may be prepared by hydrolysis ofthe corresponding phenylacetonitrile compounds of structure (25) bytechniques and procedures well known and appreciated by one of ordinaryskill in the art, such as base hydrolysis. Alternatively, thephenylacetic acid compounds may be prepared by electrochemicalcarboxylation of the corresponding benzyl halide as described in SchemeH, step h.

In step b, the appropriate α-methylphenylacetic acid ester compound ofstructure (29) is methylated to give the correspondingα,α-dimethylphenylacetic acid ester compound of structure (30) asdescribed previously in Scheme A, step a.

Alternatively α-methylphenylacetic acid ester compound of structure (29)are prepared for the corresponding α-methylphenylacetic acid compoundsby standard esterification reactions which are well known by one ofordinary skill in the art as described in step a.

Appropriate α-methylphenylacetic acid compounds may be prepared byhydrolysis of the corresponding 2-cyanoethylbenzene compound ofstructure (26) as described previously in step a. Alternatively, theα-methylphenylacetic acid compounds may be prepared by electrochemicalcarboxylation of the corresponding α-methylbenzyl halide as described inScheme H. step h.

In step c, the appropriate phenylacetic acid ester compound of structure(28) is dimethylated to give the corresponding α,α-dimethylphenylaceticacid ester compound of structure (30) as described previously in SchemeA, step c.

Alternatively α,α-dimethylphenylacetic acid ester compound of structure(30) are prepared for the corresponding α,α-dimethylphenylacetic acidcompounds by standard esterification reactions which are well known byone of ordinary skill in the art as described in step a.

Appropriate α,α-dimethylphenylacetic acid compounds may be prepared byhydrolysis of the corresponding 2-cyano-2-propylbenzene compound ofstructure (27) as described previously in step a. Alternatively, theα,α-dimethylphenylacetic acid compounds may be prepared byelectrochemical carboxylation of the corresponding α,α-dimethylbenzylhalide as described in Scheme H, step h. Appropriate α,α-dimethylbenzylhalide compounds may be prepared by hydrohalogenation of thecorresponding α-methylstyrene as described previously in Scheme C, stepe.

In step d, the appropriate phenylacetic acid ester compound of structure(28) is acylated with an appropriate ω-halo compound of the structureHal-(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined to give the correspondingω′-halo-α′-keto-phenylacetic acid ester compound of structure (34) asdescribed previously in Scheme A, step d.

In step e, the appropriate phenylacetic acid ester compound of structure(28) is acylated with an appropriate cyclopropyl compound of thestructure

wherein B is as previously defined to give the correspondingcyclopropylketo-phenylacetic acid ester compound of structure (33) asdescribed previously in Scheme A, step e.

In step f, the appropriate α-methylphenylacetic acid ester compound ofstructure (26) is acylated with an appropriate ω-halo compound of thestructure Hal-(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl,Br or I and n is as previously defined to give the correspondingω′-halo-α′-keto-α-methylphenylacetic acid ester compound of structure(30) as described previously in Scheme A, step d.

In step g, the appropriate α-methylphenylacetic acid ester compound ofstructure (29) is acylated with an appropriate cyclopropyl compound ofthe structure

wherein B is as previously defined to give the correspondingcyclopropylketo-α-methylphenylacetic acid ester compound of structure(35) as described previously in Scheme A, step e.

In step h, the appropriate α,α-dimethylphenylacetic acid ester compoundof structure (30) is acylated with an appropriate ω-halo compound of thestructure Hal-(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl,Br or I and n is as previously defined to give the correspondingω′-halo-α′-keto-α,α-di-methylphenylacetic acid ester compound ofstructure (31) as described previously in Scheme A, step d.

Appropriate α,α-dimethylphenylacetic acid ester compound of structure(30) are prepared for the corresponding α,α-dimethylphenylacetic acidcompounds by standard esterification reactions which are well known byone of ordinary skill in the art as described in step a.

Appropriate α,α-dimethylphenylacetic acid compounds may be prepared byhydrolysis of the corresponding 2-cyano-2-propylbenzene compound ofstructure (27) as described previously in step a.

In step i, the appropriate α,α-dimethylphenylacetic acid ester compoundof structure (30) is acylated with an appropriate cyclopropyl compoundof the structure

wherein B is as previously defined to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid ester compound ofstructure (32) as described previously in Scheme A, step e.

In step j, the appropriate ω-halo-α′-keto-α-methylphenylacetic acidester compound of structure (33) is methylated to give the correspondingω-halo-α′-keto-α,α-di-methylphenylacetic acid ester compound ofstructure (32) as described previously in Scheme A, step a.

In step k, the cyclopropyl functionality of the appropriatecyclopropylketo-α,α-dimethylphenylacetic acid ester compound ofstructure (32) is ring-opened to give the correspondingω′-halo-α′-keto-α,α-di-methylphenylacetic acid ester compound ofstructure (31) wherein n=3 as described previously in Scheme A, step j.

The resulting ω′-halo-α′-keto-α,α-di-methylphenylacetic acid estercompound of structure (31) wherein n=3 may be purified by distillationand/or crystallization.

In step l, the appropriate ω′-halo-α′-keto-α,α-di-methylphenylaceticacid ester compound of structure (31) wherein n=3 is ring-closed to givethe corresponding cyclopropylketo-α,α-dimethylphenylacetic acid estercompound of structure (32) as described previously in Scheme A, step k.

The resulting cyclopropylketo-α,α-dimethylphenylacetic acid estercompound of structure (32) may be purified by distillation and/orcrystallization. Additional cyclopropylketo-α,α-dimethylphenylaceticacid ester compound of structure (32) may-be recovered from the motherliquors of the crystallization by distillation.

Alternatively, additional ω′-halo-α′-keto-α,α-di-methylphenylacetic acidester compound of structure (31) wherein n=3 may be recovered from themother liquors of the crystallization by ring-closure as described instep 1 to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid ester compound ofstructure (32), purifying cyclopropylketo-α,α-dimethylphenylacetic acidester compound of structure (32) by distillation, ring-opening thepurified cyclopropylketo-α,α-dimethylphenylacetic acid ester compound ofstructure (32) as described previously in step k to give the purifiedω′-halo-α′-keto-α,α-di-methylphenylacetic acid ester compound ofstructure (31).

In step m, the appropriate ω′-halo-α′-keto-phenylacetic acid estercompound of structure (34) is dimethylated to give the correspondingω′-halo-α′-keto-α,α-di-methylphenylacetic acid ester compound ofstructure (31) as described previously in Scheme A, step c.

In step n, the appropriate ω′-halo-α′-keto-phenylacetic acid estercompound of structure (34) is methylated to give the correspondingω′-halo-α′-keto-α-methylphenylacetic acid ester compound of structure(33) as described previously in Scheme A, step a.

In step o, the cyclopropyl functionality of the appropriatecyclopropylketo-α-methyiphenylacetic acid ester compound of structure(35) is ring-opened to give the correspondingω′-halo-α′-keto-α-methylphenylacetic acid ester compound of structure(33) wherein n=3 as described previously in Scheme A, step j.

In step p, the appropriate ω′-halo-α′-keto-α-methylphenylacetic acidester compound of structure (33) wherein n=3 is ring-closed to give thecorresponding cyclopropylketo-α-methylphenylacetic acid ester compoundof structure (35) as described previously in Scheme A, step k.

In step q, the appropriate cyclopropylketo-α-methylphenylacetic acidester compound of structure (35) is methylated to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid ester compound ofstructure (32) as described previously in Scheme A, step a.

In step r, the appropriate cyclopropylketo-phenylacetic acid estercompound of structure (36) is dimethylated to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid ester compound ofstructure (32) as described previously in Scheme A, step c.

In step s, the cyclopropyl functionality of the appropriatecyclopropylketo-phenylacetic acid ester compound of structure (36) isring-opened to give the corresponding ω′-halo-α′-keto-phenylacetic acidester compound of structure (34) wherein n=3 as described previously inScheme A, step j.

In step t, the appropriate ω′-halo-α′-keto-phenylacetic acid estercompound of structure (34) wherein n=3 as is ring-closed to give thecorresponding cyclopropylketo-phenylacetic acid ester compound ofstructure (36) as described previously in Scheme A, step k.

In step u, the appropriate cyclopropylketo-phenylacetic acid estercompound of structure (36) is methylated to give the correspondingcyclopropylketo-α-methylphenylacetic acid ester compound of structure(35) as described previously in Scheme A, step a.

Starting materials for use in Scheme F are readily available to one ofordinary skill in the art.

The following examples present typical syntheses as described in SchemeF. These examples are understood to be illustrative only and are notintended to limit the scope of the present invention in any way. As usedherein, the following terms have the indicated meanings: “g” refers tograms; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 10

Step c: 2-Methyl-2-phenylpropionate, Methyl Ester

Equip a two liter, 3-necked, round bottom flask with a thermowell with athermometer, heating mantle, mechanical agitator, gas inlet for MeCl,rubber septum for sampling by syringe and a cryoscopic condensingsystem. The condensing system is composed of an 18 inch inner helicalcoil/outer jacket condenser chilled to −50 C with refrigerated acetonetopped with a dry ice cold finger having approximately 100 square inchesof chilled surface area. The cold finder is vented through a drying tubefilled with drying agent and MeCl is supplied from a lecture bottlemounted on a digital balance. The feed rate can be accurately controlledusing a needle valve and monitored by rotomter. The rotometer iscalibrated with MeCi to give an average response of 2.5 mg/min/scaledivision. Phenylacetic acid, ethyl ester is supplied via {fraction(1/16)} inch stainless steel tubing inserted through the rubber samplingseptum by a HPLC pump from a 1 liter bottle mounted on a digitalbalance. The bottle is sealed with a septum and vented through a dryingtube filled with drying agent. The temperature is controlled using athermowatch to regulate the heating mantle. If cooling is required, itis accomplished either by immersing the reaction flask in a water bathor simply by removing the mantle.

The phenylacetic acid, ethyl ester pump is primed with phenylacetic acidcontaining 1 st % t-butanol and the phenylacetic acid, ethyl esterbalance is zeroed. The MeCl balance is zoned and a 200 g sample of 60%NaH is weighed into a wide mouth plastic jar in a nitrogen filled glovebag and is transferred to the reaction vessel through a funnel (samplingseptum is removed). Through the same funnel is added anhydrous glyme(800 mL) and the septum (pierced by the {fraction (1/16)} inchphenylacetic acid, ethyl ester feed tube) is replaced. The mixture isagitated and heated to 50 C while MeCl (40 g) is introduced. When thereaction mixture reaches 50 C, the continuous addition of phenylacticacid, ethyl ester/t-butanol-at 1 mL/min and MeCl at approximately 0.62g/min. is initiated. Samples of about p.l mL are withdrawn at intervalsusing a disposable syringe fitted with an 8 inch needle. A portion ofthe sample (5-15 drops depending on the accumulation of product) isdissovled in 25% aqueous acetonitrile (5 mL) and analyzed immediately.The reaction is continued for an additional 2 hours at 50 C and then atambient temperature overnight.

In the apparatus described above, agitate NaH (180 g of 60%) andanhydrous glyme (800 mL) and heat to 50 C. Add MeCl (52 g) along withmethyl phenylacetate (20 g). Stir for 1 hour at 50 C, then add, bycontinuous addition, methyl phenylacetate (0.8 mL/min) and MeCl γapproximately 0.53 g/min). Stir for 1 hour, stop the additions andcontinue, heating for 1.5 hours. Resume the additions and run for 45minutes. Allow to agitate at ambient temperature overnight. Heat thereaction to 50 C and resume the addition of methyl phenylacetate (0.4mL/min) and MeCl (approximately 0.27 g/min). When a total of 246 g ofmethyl phenylacitate has been added, stop the addition and agitateovernight. Distill the glyme at 1 atm. until the pot temperature reaches125 C. Cool the residue and pour into water (1 L) containing acetic acid(100 mL). Filter through filter aid and separate the phases. Distill theorganic phase through a 10-plate Oldershaw column fitted with a refluxsplitting head at 4 mm Hg. Collect 10 mL at a 5:2 reflux ratio anddiscard. Collect the title compound at a 2:1 reflux ratio and headtemperature of 93 C (100 g).

EXAMPLE 11

Step d: [4-(4-Chloro-butyryl)-phenyl]-acetic Acid, Ethyl Ester and[3-(4-Chloro-butyryl)-phenyl]-acetic Acid, Ethyl Ester

Method A:

Load a 3-neck flask with sublimed AlCl₃ (293 g, 2.08 mmol) and heptane(400 mL). Cool to below 5° C. and slowly add chlorobutyryl chloride (125mL), keeping the temperature below 5° C. Add phenylethyl acetate (160mL), keeping the temperature below 10° C. and stir overnight. Decant theheptane layer and dissolve the residue in methylene chloride (400 mL).Slowly pour the methylene chloride solution into a mixture ofconcentrated hydrochloric acid (200 mL) and cracked ice. Separate theorganic phase, wash with water (1 L), followed by 5% sodium hydrogencarbonate (1 L). Evaporate the solvent in vacuo to give a red oil (243g).

Dissolve the red oil (243 g) in methylene chloride (250 mL) and spargewith hydrogen chloride gas for 1.5 hours and evaporate the solvent invacuo to give the title compound as a 50:50 mixture of para and metaisomers (243 g).

Method B:

Place aluminum chloride (293 g) and methylene chloride (300 mL) in a 1L, 3-neck round bottom flask with a thermowell and equipped with athermomter, mechanical stirrer, reflux condenser, equilibrating droppingfunnel and ice bath. Cool to 10 C and add, by dropwise addition,4-chlorobutyryl chloride (169 g), keeping the temperature below 10 C.After addition is complete, add, by dropwise addition, phenylethylacetate (164 g), keeping the temperature below 10 C. Heat the reactionto 40 C for 16 hours, slowly pour into a mechanically agistated 4 Lbeaker containing ice/water (2000 g) and stir for 1 hour. Separate thelayers, extract the water phase with methylene chloride (50 mL), filterthe combined organic phases through a ¼ inch thick bed of filter aid andextract sequentially with water (100 mL) and 10 wt % Na2CO3 (200 mL).Re-extract the carbonate solution with fresh methylene chloride (50 mL)and wash the combined methylene chloride solutions with water (100 mL).Distill off solvent at atmospheric pressure until the pot temperaturereaches 120 C. Cool the residue and dilute with 2B absolute ethanol (200mL). Beat the solution to 70 C and sparge in anhydrous HCl (20 g) over10 minutes. After 40 minutes, cool the reaction and hold overnight undernitrogen. Evaporate the solvent in vacuo to give the title compound (258g).

EXAMPLE 12

Step k: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid, EthylEster

Method A:

Dissolve 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid,ethyl ester (100 g) in xylene (500 mL) and ethanol (100 mL) and heat to70° C. Sparge the atmosphere of the reaction with hydrogen chloride gas(24.6 g) over 220 hours. Evaporate the solvent in vacuo to give thetitle compound.

Method B:

Add a solution of 5M HCl in acetonitrile (50 mL, 9 g of HCl, 247 mmol)to 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester (25.5 g, 98 mmol) and seal in a 100 mL flask with a rubber septum.Heat to 50° C. for 4 hours, dilute with toluene (50 mL), wash with water(50 mL), aqueous 10% Na2CO3 (50 mL) and then water (50 mL). Evaporatethe solvent in vacuo to give the title compound as an oil (27.2 g).

Method C:

Place 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester (86 g, 330 mmol) and dry acetonitrile (70 mL) in a 250 mL 3-neckround-bottom flask equipped with a magnetic stirbar, thermometoer, gasinlet and distillation head connected to a balloon by way of a T fittingfor pressure control. Slowly warm the reaction mixture with stirring to60° C. while sparging excess HCl into the reaction mixture for 6 hours,dilute with toluene (50 mL), wash with water (50 mL), aqueous 10% Na2CO3(50 mL) and then water (50 mL). Evaporate the solvent in vacuo to givethe title compound.

Method D:

Place 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester (91 g, 350 mmol) in a 1 L 3-neck round-bottom flask equipped witha magnetic stirbar, thermometer, gas inlet, and distillation headconnected to a balloon by way of a T fitting for pressure control.Slowly sparge in anhydrous HCl, keeping the balloon slightly inflated.After 10 minutes, add acetonitrile (590 mL), heat to 65° C. and addexcess HCl over 7 hours. Heat the mixture and remove acetonitrile/HCloverhead. After 500 mL of acetonitrile is removed, add mixed xylene (200mL) and continue the distillation. Add additional xylene (200 m) andafter a total of 640 mL of solvent has been removed (pot=130° C. andoverhead=130 C°), add ethanol 2B (100 mL). Remove the ethanol bydistillation to give the title compound as a oil (330 g).

Method E:

Place 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester (98 g, 410 mmol) and xylenes (600 mL) in a 1 L 3-neck round-bottomflask equiped with a magnetic stirbar, thermomoter, gas inlet anddistillation head connected to a balloon by way of a T fitting forpressure control. Heat the reaction mixture to 80° C. and slowly spargein anhydrous HCl. After 100 minutes, add ethanol 2B (100 mL) and HCl (26g) and heat to 35° C. for 2 hours. Remove the ethanol and HCl bydistillation with aspirator vacuum (pot=35° C., overhead=30° C.) to givethe title compound as a solution in xylene.

Method F:

Place 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester (500 g) in a 4 L Hastelloy reactor equipped with a gas inlet,overhead stirrer, temperature control and dip pipe for sampling. Heatthe oil to 60 C and evacuate the head space. Add HCl raising thepressure to 10 psig and react for 80-300 minutes. Vent the excess HCland sparge the oil with nitrogen for 5 minutes to give the titlecompound.

Method G:

Fit a 2 L 3-neck round bottom flask with an overhead paddle stirrer, agas sparge tube (with fritted end to disperse gas) and a refluxcondenser (with drying tube on top, filled with drying agent). Fit thebottom of 1o the flask with a heating mantle and put2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester(78.10 g, 0.300 mol), xylenes (400 mL) and absolute 2B ethanol (90 mL)into the flask. Stir to dissolve all the solids at ambient temperature.Sparge hydrogen chloride from a lecture bottle (38.36 g, 1.052 mol) intothe stirred solution without external heating over a 15 minute period.Replace the sparge tube with a glass stopper and heat the solution bymantle, with stirring, at 40-79 C for 45 minutes and 79 C for 15minutes. Replace the reflux condenser with a simple still head fittedwith a thermometer and condenser. Collect 200 mL of distillate (80-138 Cat atmospheric pressure) and allow the remaining light yellow solutionto cool to give a mixture of the title compound and xylenes.

EXAMPLE 13

Step t: (4-Cyclopropanecarbonyl-phenyl)-acetic Acid, Ethyl Ester and(3-Cyclopropanecarbonyl-phenyl)-acetic Acid, Ethyl Ester

Dissolve the mixture of [4-(4-chloro-butyryl)-phenyl]-acetic acid, ethylester and [3-(4-chloro-butyryl)-phenyl]-acetic acid, ethyl ester (650 g)in 2B ethanol (1250 mL). Add, by dropwise addition, a solution of 2Bethanolic KOH (168 g in 1000 mL), keeping the temperature below 10 C.After the addition, stir magnetically for 5 hours at −10° C. Bring themixture to pH 6 with acetic acid (5 mL) and filter through a celitepre-coat. Evaporate the solvent in vacuo to give the title compound asan oil (538 g).

EXAMPLE 14

Step d: [4-(4-Chloro-butyryl)-phenyl]-acetic Acid, 2-ethylhexyl Ester

Mix 2-ethyl-1-hexanol (6.5 g, 5 mol), triethylamine (50.5 g, 0.5 mol)and methylene chloride (50 mL). Add, by dropwise addition,2-phenylacetyl chloride (5 mol) and warm to 50° C. Stir at roomtemperature overnight, filter and wash the filtercake with methylenechloride (50 mL). Combine the organic phases and wash with 5% aqueoushydrochloric acid (50 mL) and water. Dry (MgSO₄), evaporate the solventin vacuo and purify by distillation to give 2-phenylacetic acid,2-(2-ethylhexy)l ester.

Mix chlorobutyryl chloride (16.9 g) and AlCl₃ (29.3 g) at roomtemperature. Add 2-phenylacetic acid, 2-ethylhexyl ester (27.6 g),keeping the temperature below 10° C. Heat at 35° C. for 24 hours, quenchin ice water (200 g). Separate the organic phase, dry (MgSO₄) andevaporate the solvent in vacuo. Dilute the residue with ethanol (150mL), add hydrogen chloride (5 g) and heat to 75° C. After 2.5 hours, addanother 5 g of hydrogen chloride and stir at 75° C. for 24 hours.Evaporate the solvent in vacuo to give the title compound.

EXAMPLE 15

Step h: 2-[4-(4-Chloro-butyrl)-phenyl]-2-methyl-proprionic Acid, EthylEster and 2-[3-(4-Chloro-butyrl)-phenyl]-2-methyl-proprionic Acid, EthylEster

Method A:

Place aluminum chloride (58.4 g, 438 mmol) and methylene chloride (100mL) in a 250 mL 3 neck flask equipped with a condenser, thermometer, andoverhead stirrer. Cool to 10 C and add, by dropwise addition,4-chlorobutyryl chloride (32.4 g, 230 mmol), keeping the temperaturebelow 10 C. Add, by dropwise addition, ethyl dimethylphenylacetate (40g, 208 mmol) at 10 C. After the addition, slowly warm the mixture toroom temperature and then heat at reflux for 17 hours. Quench thereaction into ice (400 g) and stir for 1 hour. Extract with methylenechloride (2×25 mL), wash with water (25 mL), 10% aqueous sodiumcarbonate (25 mL) and water (25 mL). Evaporate the solvent in vacuo togive a red oil γ58.7 g).

Dissolve the red oil (58.7 g) in 2B ethanol (40 mL) and place in a 250mL round bottom flask equipped with an overhead stirrer, condenser,thermometer and gas inlet tube. Add anhydrous HCl (3 g. 80 mmol) withvigorous stirring and heat to 70 C for 1 hour. Evaporate the solvent invacuo to give the title compound as a yellow oil (59 g).

Method B:

Place AlCl₃ (146.5 g. 1.1 mol) and methylene chloride (75 mL) in a3-neck, 500 mL round-bottomed flack equipped with an overhead stirrer,bottom drop valve, thermometer, condenser and temperature control andcool to 15° C. Add, by dropwise addition, 4-chlorobutyryl chloride (84.5g, 0.6 mol), keeping the temperature below 15° C. Add, by dropwiseaddition, ethyl 2-methyl-2-phenylpropionate (96 g, 0.5 mol), keeping thetemperature below 15° C. After addition is complete, stir the reactionmixture at 22° C. for 1 hour, then heat at reflux (57° C.) for 2 hours.Add the reaction mixture, by dropwise addition, by way of the bottomdrop valve, to water (500 mL) at 95° C. contained in a 2 L 3 neck flaskequipped with a magnetic stirbar, thermometer and distillation head.During addition, hold the reaction mixture at 70° C. by allowing themethylene chloride to distill overhead. After the quench is complete,separate the the organic layer, dry (MgSO₄) and evaporate the solvent invacuo to give the title compound (150 g).

EXAMPLE 16

Step h: 2-[4-(4-Chloro-butyrl)-phenyl]-2-methyl-proprionic Acid, MethylEster

Method A:

Mix AlCl₃ (128 g) and methylene chloride (66 mL) and cool with a dryice/acetone bath to −15 C. Add, by dropwise addition, 4-chlorobutyrylchloride (73.8 g), keeping the temperature below 15 C. Add, by dropwiseaddition, methyl 2-methyl-2-phenylpropionate (77.8 g), keeping thetemperature below 15 C. After addition is complete, stire the reactionmixture at 22 C for 10 minutes, then heat to 45 C for 3 hours. Quenchinto ice/water (875 g), filter through filter aid, separate the layersand wash the aqueous phase with methylene chloride (50 mL). Combine theorganics and evaporate the solvent in vacuo to give 131 g. Decant solidsoff and place the oil in a 500 mL. 3-neck flask along with methanol (150mL). Purge with HCl and heat at reflux for 1 hour and allow to standovernight. Evaporate the solvent in vacuo, dissolve in methylenechloride (250 mL), wash with water (200 mL) and NaHCO3 (300 mL).Evaporate the solvent in vacuo to give a mixture of2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl esterand 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methylester (approximately m:p 50:50) (121 g).

Place the mixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionicacid, methyl ester and2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester(approximately m:p 50:50) (40.1 g) in a 250 mL, 3-necked flask with amechanical agitator, N₂ blanket and cooling bath. Add methanol (80 mL)at room temperature and cool to −5 C with and ice/acetone/water bath.Seed with 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid,methyl ester and allow to stand at −5 C for 1 hour. Cool to −10 C. withice/acetone and allow to stand for 1.5 hours. Cool to −16 C and hold for30 minutes. Vacuum filter through a 60 mL sintered glass jacketed filterfunnel chilled to −10 C. Wash the filtercake with cold (−50 C) methanol(30 mL) and cold (−50 C) n-pentane (30 mL). Dry the filtercake brieflyin a stream of nitrogen and vacuum dry (20 C at 15 mm Hg) to give themixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid,methyl ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionicacid, methyl ester (approximately m:p 10:90) (10.5 g).

Dissolve the mixture of2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl esterand 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methylester (approximately m:p 10:90) in methanol (30 mL), cool to 10 C in anice/water bath and seed with2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester.Cool to 0 C and hold for 20 minutes. Vacuum filter, wash and dry asabove to give the title compound (5.6 g) as an off-white solid; mp29.5-30.5 C.

Method B:

Mix AlCl₃ (1289) and methylene chloride (66 mL) and cool with a dryice/acetone bath to −15 C. Add, by dropwise addition, 4-chlorobutyrylchloride (73.8 g), keeping the temperature below 15 C. Add, by dropwiseaddition, methyl 2-methyl-2-phenylpropionate (77.8 g), keeping thetemperature below 15 C. After addition is complete, stire the reactionmixture at 22 C for 10 minutes, then heat to 45 C for 3 hours. Quenchinto ice/water (875 g), filter through filter aid, separate the layersand wash the aqueous phase with methylene chloride (50 mL). Combine theorganics and evaporate the solvent in vacuo to give 131 g. Decant solidsoff and place the oil in a 500 mL 3-neck flask along with methanol (150mL). Purge with HCl and heat at reflux for 1 hour and allow to standovernight. Evaporate the solvent in vacuo, dissolve in methylenechloride (250 mL), wash with water (200 mL) and NaHCO₃ (300 mL).Evaporate the solvent in vacuo to give a mixture of2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl esterand 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methylester (121 g) (approximately 50:50 m:p).

Place the mixture of 2-[4-(4-chloro-butyrl)-phenyl]-2ethyl-proprionicacid, methyl ester and2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester(approximately 50:50 m:p) (40.1 g) is a 250 mL, 3-necked flask with amechanical agitator, N₂ blanket and cooling bath. Add methanol (80 mL)at room temperature and cool to −5 C with and ice/acetone/water bath.Seed with 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid,methyl ester and allow to stand at −5 C for 1 hour. Cool to −10 C. withice/acetone and allow to stand for 1.5 hours. Cool to −16 C and hold for30 minutes. Vacuum filter through a 60 mL sintered glass jacketed filterfunnel chilled to −10 C. Wash the filtercake with cold (−50 C) methanol(30 mL) and cold (−50 C) n-pentane (30 mL). Dry the filtercake brieflyin a stream of nitrogen and vacuum dry (20 C at 15 mm Hg) to give themixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid,methyl ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionicacid, methyl ester (approximately 10:90 m:p) (10.5 g).

To the methanol solution of the mixture of2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl esterand 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methylester (approximately 50:50 m:p) (approximately 70:30 m:p) fromcrystallization (i.e. mother liquor), slowly add 1 to 1.2 equivalents of25% NaOMe/MeOH solution. Agitate for approximately 30 minutes at 25 C.Neutralize the excess NaOMe with excess carbon dioxide. Add water (300mL) per mole of subtrate, evaporate the methanol by vacuum distiallationand decant the aqueous layer to give a mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methylester (approximately 70:30 m:p).

Distill the mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methylester (approximately 70:30 m:p) at 0.5 mm Hg and discard a lightfraction boiling at 25-130 C (pot temp −105-165 C). Continue distillingthe oil at 0.5 mm Hg and collect a second fraction boiling at 130-150 C(pot temperature 165-190) to give the mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methylester (approximately 70:30 m:p).

Pack a 31/32 in. I.D. vacuum jacked and silvered column with 53 inchesof 1 in. diameter, 316 stainless steel packing. For high temperaturedistillation, the column is fitted with an adiabatic jacket composed ofan inner layer of 1 in. fiber glass wrapped with heat tape in an upperand lower zone and finally covered with 2 in. fiber glass insulation.The upper zone is heated at 135 C and the lower zone at 185 C. Themagnetic reflux splitting head is controlled by a reflux timer andfitted with a standard thermometer for monitoring overhead temperature.Vacuum is supplied by a system composed of a pump protected by a dry icetrap and fitted with a McLeod gage for monitoring the overhead pressure.The 1 L distillation pot is heated with an electric mantel at 65 volts,agitated magnetically and fitted with a mercury manometer for monitoringbottoms pressure, and a thermocouple for monitoring bottoms temperature.

The still pot is charged with 265 g each of m- and p-xylene and fittedwith a rubber septum for sampling by syringe. The xylene mixture isheated at total reflux and atmosphere pressure with the temperature 135C at the head and 139 C in the bottoms. Samples are withdrawn foranalysis by collecting a few drops of distillate and extracting about 1mL from the pot. The still is sampled after 3 hours and again after 18hours for calibration by GC and theoretical plate calculations using theFenske correlation and a relative volatility, α=1.0209.

Charge the mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methylester (approximately 70:30 m:p) to the still pot and neat at totalreflux until the column has equilibrated. Take a forecut at 2:1 refluxratio and increase the reflux ratio to 5:1 and the2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl esterstripped. Cool and release vacuum and allow to sit overnight. Addbis(2-ethylhexyl)phthalate (dioctyl phthalate) (100 mL) to the still potand restart the still as before. Once the still has equilibrated,collect mixed fractions of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methylester at 50:50 reflux ratio.

Place the mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methylester (approximatelty m:p 50:50) (330 mmol) and dry acetonitrile (70 mL)in a 250 mL 3-neck round-bottom flask equipped with a magnetic stirbar,thermometoer, gas inlet and distillation head connected to a balloon byway of a T fitting for pressure control. Slowly warm the reactionmixture with stirring to 60° C. while sparging excess HCl into thereaction mixture for 6 hours, dilute with toluene (50 mL), wash withwater (50 mL), aqueous 10% Na2CO3 (50 mL) and then water (50 mL).Evaporate the solvent in vacuo to give the mixture of2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl esterand 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methylester (121 g) (approximately 50:50 m:p).

Place the mixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionicacid, methyl ester and2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester(approximately 50:50 m:p) (40.1 g) in a 250 mL, 3-necked flask with amechanical agitator, N₂ blanket and cooling bath. Add methanol (80 mL)at room temperature and cool to −5 C with and ice/acetone/water bath.Seed with 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid,methyl ester and allow to stand at −5 C for 1 hour. Cool to −10 C. withice/acetone and allow to stand for 1.5 hours. Cool to −16 C and hold for30 minutes. Vacuum filter through a 60 mL sintered glass jacketed filterfunnel chilled to −10 C. Wash the filtercake with cold (−50 C) methanol(30 mL) and cold (−50 C) n-pentane (30 mL). Dry the filtercake brieflyin a stream of nitrogen and vacuum dry (20 C at 15 mm Hg) to give themixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid,methyl ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionicacid, methyl ester (approximately 10:90 m:p) (10.5 g).

Dissolve the mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methylester (approximately 10:90 m:p) in methanol (30 mL), cool to 10 C in anice/water bath and seed with2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester.Cool to 0 C and hold for 20 minutes. Vacuum filter, wash and dry asabove to give the title compound (5.6 g) as an off-white solid; mp29.5-30.5 C.

EXAMPLE 17

Step l: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic Acid, EthylEster

Dissolve a mixture of2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-proprionic acid, ethyl esterand 2-[3-(4-chloro-butyryl)-phenyl]-2-methyl-proprionic acid, ethylester (59 g) in 2B ethanol (100 mL) and add, by dropwise addition, asolution of KOH (49.4 g of 85%) in 2B ethanol (250 mL), keeping thetemperature below 15 C. After the addition, warm the reaction mixture toroom temperature and stir magentically for 1 hour. Bring to pH 6 withacetic acid and filter through a celite pre-coat. Evaporate the solventin vacuo to give a mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester as an oil (57.1 g) Purify by one of the following methods:

Method A:

Pack a 31/32 in. I.D. vacuum jacked and silvered column with 53 inchesof 1 in. diameter, 316 stainless steel packing. For high temperaturedistillation, the column is fitted with an adiabatic jacket composed ofan inner layer of 1 in. fiber glass wrapped with heat tape in an upperand lower zone and finally covered with 2 in. fiber glass insulation.The upper zone is heated at 135 C and the lower zone at 185 C. Themagnetic reflux splitting head is controlled by a reflux timer andfitted with a standard thermometer for monitoring overhead temperature.Vacuum is supplied by a system composed of a pump protected by a dry icetrap and fitted with a McLeod gage for monitoring the overhead pressure.The 1 L distillation pot is heated with an electric mantel at 65 volts,agitated magnetically and fitted with a mercury manometer for monitoringbottoms pressure, and a thermocouple for monitoring bottoms temperature.

The still pot is charged with 265 g each of m- and p-xylene and fittedwith a rubber septum for sampling by syringe. The xylene mixture isheated at total reflux and atmosphere pressure with the temperature 135C at the head and 139 C in the bottoms. Samples are withdrawn foranalysis by collecting a few drops of distillate and extracting about 1mL from the pot. The still is sampled after 3 hours and again after 18hours for calibration by GC and theoretical plate calculations using theFenske correlation and a relative volatility, α=1.0209.

Charge the mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester (901.2 g) to the still pot and heat at total reflux until thecolumn has equilibrated. Take a forecut at 2:1 reflux ratio and increasethe reflux ratio to 5:1 and the2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl esterstripped. Cool and release vacuum and allow to sit overnight. Addbis(2-ethylhexyl)phthalate (dioctyl phthalate) (100 mL) to the still potand restart the still as before. Once the still has equilibrated,collect mixed fractions of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester at 10:1 reflux ratio. Once the overheads are free of2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl esterby GC analysis, reduce the reflux ratio to 2:1 and collect the titlecompound.

Method B:

Place crude mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester (4872 g) on a rotary evaporator and strip of vaolatives to an endpoint of 85 C, 15 mm to give a brown oil (4006 g). Charge a 3 L roundbottom three neck flask equipped with magnetic stirbar, thermometer anddistillation head with stripped crude mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester. Distill the oil at 0.5 mm Hg and discard a light fraction boilingat 25-130 C (pot temp −105-165 C, 9.5 g). Continue distilling the oil at0.5 mm Hg and collect a second fraction boiling at 130-150 C (pottemperature 165-190, 3217 g).

Place the crude flash distilled product (1000 g) in a 4 L Hastelloyreactor equipped with Camille control along with water (500 mL) andethanol 2B (2 L). Heat the mixture to 40 C while agitating at 400 rpm.Set the reactor jacket to cool the contents at approximately 12 C/hourto a final temperature of 0 C after a clear solution is observed. Thenset the jacket to cool the reactor contents at approximately 12 C/hourto a final temperature of −15 C and hold at that temperature for morethan one hour. Filter the slurry, wash with cold (−15 C) ethanol, coldheptanes (−15 C) and dry to give a solid (507 g). Purify byrecrystallization from mixed heptanes as above to give the titlecompound (503 g) after drying.

Recycle:

Pack a 31/32 in. I.D. vacuum jacked and silvered column with 53 inchesof 1 in. diameter, 316 stainless steel packing. For high temperaturedistillation, the column is fitted with an adiabatic jacket composed ofan inner layer of 1 in. fiber glass wrapped with heat tape in an upperand lower zone and finally covered with 2 in. fiber glass insulation.The upper zone is heated at 135 C and the lower zone at 185 C. Themagnetic reflux splitting head is controlled by a reflux timer andfitted with a standard thermometer for monitoring overhead temperature.Vacuum is supplied by a system composed of a pump protected by a dry icetrap and fitted with a McLeod gage for monitoring the overhead pressure.The 1 L distillation pot is heated with an electric mantel at 65 volts,agitated magnetically and fitted with a mercury manometer for monitoringbottoms pressure, and a thermocouple for monitoring bottoms temperature.

The still pot is charged with 265 g each of m- and p-xylene and fittedwith a rubber septum for sampling by syringe. The xylene mixture isheated at total reflux and atmosphere pressure with the temperature 135C at the head and 139 C in the bottoms. Samples are withdrawn foranalysis by collecting a few drops of distillate and extracting about 1mL from the pot. The still is sampled after 3 hours and again after 18hours for calibration by GC and theoretical plate calculations using theFenske correlation and a relative volatility, α=1.0209.

Charge the still pot with the mother liquors from the crystallization ofthe mixture of 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionicacid, ethyl ester and2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester(759 g, 14.7 wt % p-isomer). Distill as described above to give 510 goverhead at a 5:1 reflux ratio (0.2 mm bottom pressure, 7-13 mm overheadpressure, 182-205 C bottom temperature, 92-144 C overhead temperature).Save the bottoms (214 g, 52 wt % p-isomer) for recycle.

Charge a 250 ml round bottom flask equipped with a distillation head,thermometer, and magnetic stirbar with 190 g of the saved bottoms fromabove. Flash distill, retaining the fraction boiling at 149-165 C (0.6mm, pot temperature=159-190 C) to give 178 g (50.5% p-isomer). Mix flashdistilled material (981 g) with material obtained from the recycle flashdistillation (108 g) to give 1100 g of recycle material forcrystallization. Crystallize 92.5 g (94 wt % p-isomer) from 25%water-ethanol to give the title compound (39.7 g) after drying.

EXAMPLE 18

Step h and step l: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionicacid, ethyl ester and2-(3-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic Acid, Ethyl Ester

Method A:

Place aluminum chloride (586 g, 4.4 moles) and methylene chloride (300mL) in a 2 L 3-neck round bottom flask equipped with an overheadstirrer, dry ice condenser, and nitrogen atmosphere. Cool to 10 C andadd, by dropwise addition, chlorobutyryl chloride (338 g, 2.4 moles),keeping the temperature below 15 C. After addition is complete, add, bydropwise addition, ethyl 2-methyl-2-phenylpropionate (384 g, 2 mol),keeping the temperature below 15 C. After addition was complete, warmthe reaction mixture to 22 C and stir for 1 hour. Raise the temperatureto 90 C, stir for 90 minutes, cool to room temperature and slowly pourinto a 6 L stirred flask containing ice/water (4 kg). Filter through acelite precoat, separate the organic phase and wash the aqueous phasewith methylene chloride (50 mL). Evaporate the solvent in vacuo to givea mixture of 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-proprionic acid,ethyl ester and 2-[3-(4-chloro-butyryl)-phenyl]-2-methyl-proprionicacid, ethyl ester.

Dissolve the mixture of2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-proprionic acid, ethyl esterand 2-[3-(4-chloro-butyryl)-phenyl]-2-methyl-proprionic acid, ethylester in 2B ethanol (400 mL) and place in a 3 L 3-neck round bottomflask equipped with an overhead stirrer, gas inlet and reflux condenser.Add anhydrous HCl (50 g) and stir the mixture at 70 C for 1 hour. Coolthe solution to 15 C and add, by dropwise addition, aqueous 50% NaOH(260 g), keeping the temperature below 15 C. After the addition, stirthe mixture an addition 1 hour at 22 C. Add toluene (700 mL) followed byacetic acid (2 g) and then water (500 mL). Separate the layers andevaporate the solvent in vacuo to give the title compound as a yellowoil (551 g).

Method B:

Place aluminum chloride (458 g, 3.4 mole) and methylene chloride (234mL) in a 2 L 3neck round bottom flask equipped with an overhead stirrer,dry ice condenser and nitrogen atmosphere. Cool to 10 C and add, bydropwise addition, 4-chlorobutyryl chloride (264 g, 1.9 mol), keepingthe temperature below 15 C. After addition is complete, add, by dropwiseaddition, ethyl 2-methyl-2-phenylpropionate (300 g, 1.56 mol), keepingthe temperature below 15 C. After the addition is complete, warm thereaction mixture to 24 C and stir for 1 hour. Raise the temperature to57 C for 2 hours, cool to room temperature and slowly pour into a 6Lstirred flask containing ice/water (3.1 kg). Filter through a celiteprecoat and separate the phases. Evaporate the solvent in vacuo to givean oil.

Dissolve the oil in 2B ethanol (312 mL) and place in a 3 L 3 neck roundbottom flask equiped with an overhead stirrer, gas inlet and refluxcondenser. Add anhydrous HCl (39 g) and stir the mixture at 70 C for 1hour. Cool to 50 C and add, by dropwise addition, aqueous 20% NaOH (641g), keeping the temperature below 50 C. After the addition, stir themixture for an additional 1 hour at 50 C, cool to room temperature andneutralize with acetic acid (6.25 g). Separate the layers and evaporatethe solvent in vacuo to give the title compound (391 g).

EXAMPLE 19

Step h and step l: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionicAcid, 2-ethylhexyl Ester

Mix methylene chloride (50 mL), 2-ethylhexyl alcohol (130 g, 1 mol) andtriethylamine (50 g, 0.5 mol). Add, by dropwise addition, ethyldimethylphenylacetyl chloride (91 g, 0.5 mol). Heat the reaction mixtureto 68 C for 1 hour, add methylene chloride (100 mL) and stir overnight.Remove the solids by filtration, wash with methylene chloride (50 mL),combine with the liquid organics, wash with aqueous 5% HCl, (50 mL),water (50 mL) and dry over MgSO₄. Evaporate the solvent in vacuo andpurify by distillation (119 C at 1 mmHg) (105 g, 76%).

Place aluminum chloride (29.3 g) and methylene chloride (30 mL) in a 250mL round bottom flask with an overhead stirrer, temperature control,condenser, additonal funnel and nitrogen atmosphere. Add, by dropwiseaddition, chlorobutyryl chloride (16.9 g), keeping the temperature below10 C. After addition is complete, warm the reaction mixture to 36 C andhold for 24 hours. Quench the reaction mixture into ice/water (200 g)and extract with methylene chloride (50 mL). Wash the organics withwater (50 mL) and dry (MgSO₄). Evaporate the solvent in vacuo to give anoil (30 g). Place the oil in a 250 mL flask equipped with an overheadstirrer, gas inlet, condenser and thermometer. Add 2B ethanol (150 mL)followed by anhydrous HCl (5 g). Heat the reaction mixture to 76 C for2.5 hours then add additional HCl (5 g). Heat the reaction mixture at 76C for 22 hours, evaporate the solvent in vacuo to give an oil. Dissolvethe oil in 2B ethanol (100 mL), treat with solid KOH (10 g) and heat atreflux for 2 hours.

EXAMPLE 20

Step m and step l: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionicAcid, Ethyl Ester

Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-acetic acid, ethyl ester (28.5g) in toluene (50 mL) and evaporate the solvent in vacuo to removetraces of ethanol. Dissolve the residue in diglyme (50 mL) and add, bydropwise addition, to a suspension of sodium hydride (12.2 g of a 60%suspension in mineral oil) slurried in diglyme (150 mL) containingmethyl chloride (10 g). Slowly add methyl chloride (10 g) and stir for15 minutes. Filter through filter aid, wash filtercake with acetonitrileand evaporate the solvent. Remove meta-isomer by distillation (150° C.@1mm) and crystallize (ethanol) to give the title compound (93%).

EXAMPLE 21

Step f and step: 2-(4-Cyclopropanecarbonyl-phenyl)-propionic Acid, EthylEster and 2-(3-Cyclopropanecarbonyl-phenyl)-propionic Acid, Ethyl Ester

Dissolve 2-phenylpropionic acid (30 g) in 2B ethanol (100 mL and addanhydrous HCl (10 g). Allow to sit for 48-72 hours, evaporate thesolvent in vacuo and purify by distillation to give ethyl2-phenylpropionate (31 g); bp 100 C at 6 mm.

Place aluminum chloride (49.4 g, 0.371mole) and methylene chloride (50mL) in a 250 mL 3-neck round bottom flask equipped with an overheadstirrer, addition funnel and thermometer. Cool to less then 10 C andadd, by dropwise addition, chlorobutyrylchloride (23.8 g, 0.202 mol),keeping the temperature below 10 C. After addition is complete, add, bydropwise addition, ethyl 2-phenylpropianate (30 g, 0.17 mol), keepingthe temperature below 10 C. Stir at room temperature for 1 hour thenheat at reflux for 14 hours. Quench into ice/water (350 g) and filterthrough a celite pre-coat. Separate the layers and evaporate the solventin vacuo to give a red oil.

Dissolve the red oil in 2B ethanol (35 mL) and place in a round bottomflask with a condenser and gas inlet. Add anhydrous HCl (4.3 g) and heatthe solution to 70 C for 1 hour. Cool the solution to 10 C and add, bydropwise addition, 20% aqueous sodium hydroxide. Separate the layers andevaporate the solvent in vacuo to give an oil.

Re-treat the oil with HCl in 2B ethanol as above, cool to 10 C and treatwith a 20% solution of sodium ethoxide in ethanol. Neutralize withacetic acid, filter the solids and evaporate the solvent in vacuo.Purify by distillation to give the title compound; bp 161-167 at 1.2 mm.

The novel intermediates of formula (II), formula (III), formula (IV),formula (V), formula (VI) and formula (VII) wherein R₅ is CONR₆R₇ mayalso be prepared as described in Scheme G. In Scheme G, all substituentsare as previously defined unless otherwise indicated.

Scheme G provides alternative various general synthetic procedures forpreparing the novel intermediates of formula (II), formula (III),formula (IV), formula (V), formula (VI) and formula (VII) wherein R₅ isCONR₆R₇.

In step a, the appropriate phenylacetic acid amide compound of structure(37) is methylated to give the corresponding α-methylphenylacetic acidamide compound of structure (38) as described previously in Scheme A,step a.

Appropriate phenylacetic acid amide compound of structure (37) areprepared from the corresponding phenylacetic acid by standardamide-forming reactions as are known in the art. The appropriatephenylacetic acids may be prepared by hyrdolysis of the corresponding2-cyano-2-propylbenzene compound of structure (27) by techniques andprocedures well known and appreciated by one of ordinary skill in theart.

In step b, the appropriate α-methylphenylacetic acid amide compound ofstructure (38) is methylated to give the correspondingα,α-dimethylphenylacetic acid amide compound of structure (39) asdescribed previously in Scheme A, step a.

Appropriate α-methylphenylacetic acid amide compound of structure (38)are prepared from the corresponding α-methylphenylacetic acid bystandard amide-forming reactions as are known in the art as as describedin step a.

In step c, the appropriate phenylacetic acid amide compound of structure(37) is dimethylated to give the corresponding α,α-dimethylphenylaceticacid amide compound of structure (39) as described previously in SchemeA, step c.

In step d, the appropriate phenylacetic acid amide compound of structure(37) is acylated with an appropriate ω-halo compound of the structureHal-(CH2)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined to give the correspondingω′-halo-α′-keto-phenylacetic acid amide compound of structure (43) asdescribed previously in Scheme A, step d.

In step e, the appropriate phenylacetic acid amide compound of structure(37) is acylated with an appropriate cyclopropyl compound of thestructure

wherein B is as previously defined to give the correspondingcyclopropylketo-phenylacetic acid amide compound of structure (45) asdescribed previously in Scheme A, step e.

In step f, the appropriate α-methylphenylacetic acid amide compound ofstructure (38) is acylated with an appropriate ω-halo compound of thestructure Hal-(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl,Br or I and n is as previously defined to give the correspondingω′-halo-α′-keto-α-methylphenylacetic acid amide compound of structure(42) as described previously in Scheme A, step d.

In step g, the appropriate α-methylphenylacetic acid amide compound ofstructure (38) is acylated with an appropriate cyclopropyl compound ofthe structure

wherein B is as previously defined to give the correspondingcyclopropylketo-α-methylphenylacetic acid amide compound of structure(44) as described previously in Scheme A, step e.

In step h, the appropriate α,α-dimethylphenylacetic acid amide compoundof structure (39) is acylated with an appropriate ω-halo compound of thestructure Hal-(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl,Br or I and n is as previously defined to give the correspondingω′-halo-α′-keto-α,α-di-methylphenylacetic acid amide compound ofstructure (40) as described previously in Scheme A, step d.

Appropriate α,α-dimethylphenylacetic acid amide compound of structure(39) are prepared from the corresponding α,α-dimethylphenylacetic acidby standard amide-forming reactions as are known in the art as asdescribed in step a.

In step i, the appropriate α,α-dimethylphenylacetic acid amide compoundof structure (39) is acylated with an appropriate cyclopropyl compoundof the structure

wherein B is as previously defined to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid amide compound ofstructure (41) as described previously in Scheme A, step e.

In step j, the appropriate ω′-halo-α′-keto-α-methylphenylacetic acidamide compound of structure (42) is methylated to give the correspondingω′-halo-α′-keto-α,α-di-methylphenylacetic acid amide compound ofstructure (40) as described previously in Scheme a, step a.

In step k, the cyclopropyl functionality of the appropriatecyclopropylketo-α,α-dimethylphenylacetic acid amide compound ofstructure (41) is ring-opened to give the correspondingω′-halo-α′-keto-α,α-di-methylphenylacetic acid amide compound ofstructure (40) wherein n=3 as described previously in Scheme A, step j.

In step l, the appropriate ω′-halo-α′-keto-α,α-di-methylphenylaceticacid amide compound of structure (40) wherein n=3 is ring-closed to givethe corresponding cyclopropylketo-α,α-dimethylphenylacetic acid amidecompound of structure (41) as described previously in Scheme A, step k.

In step m, the appropriate ω′-halo-α′-keto-phenylacetic acid amidecompound of structure (43) is dimethylated to give the correspondingω′-halo-α′-keto-α,α-di-methylphenylacetic acid amide compound ofstructure (40) as described previously in Scheme A, step c.

In step n, the appropriate ω′-halo-α′-keto-phenylacetic acid amidecompound of structure (43) is methylated to give the correspondingω′-halo-α′-keto-α-methylphenylacetic acid amide compound of structure(42) as described previously in Scheme A, step a.

In step o, the cyclopropyl functionality of the appropriatecyclopropylketo-α-methylphenylacetic acid amide compound of structure(44) is ring-opened to give the correspondingω′-halo-α′-keto-α-methylphenylacetic acid amide compound of structure(42) wherein n=3 as described previously in Scheme A, step J.

In step p, the appropriate ω′-halo-α′-keto-α-methylphenylacetic acidamide compound of structure (42) wherein n=3 is ring-closed to give thecorresponding cyclopropylketo-α-methylphenylacetic acid amide compoundof structure (44) as described previously in Scheme A, step k.

In step q, the appropriate cyclopropylketo-α-methylphenylacetic acidamide compound of structure (44) is methylated to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid amide compound ofstructure (41) as described previously in Scheme A, step a.

In step r, the appropriate cyclopropylketo-phenylacetic acid amidecompound of structure (45) is dimethylated to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid amide compound ofstructure (41) as described previously in Scheme A, step c.

In step s, the cyclopropyl functionality of the appropriatecyclopropylketo-phenylacetic acid amide compound of structure (45) isring-opened to give the corresponding ω′-halo-α′-keto-phenylacetic acidamide compound of structure (43) wherein n=3 as described previously inScheme A, step j.

In step t, the appropriate ω-halo-α′-keto-phenylacetic acid amidecompound of structure (43) wherein n=3 is ring-closed to give thecorresponding cyclopropylketo-phenylacetic acid amide compound ofstructure (45) as described previously in Scheme A, step k.

In step u, the appropriate cyclopropylketo-phenylacetic acid amidecompound of structure (45) is methylated to give the correspondingcyclopropylketo-α-methylphenylacetic acid amide compound of structure(44) as described previously in Scheme A, step a.

Starting materials for use in Scheme G are readily available to one ofordinary skill in the art.

The following example present typical syntheses as described in SchemeG. These examples are understood to be illustrative only and are notintended to limit the scope of the present invention in any way. As usedherein, the following terms have the indicated meanings: “g” refers tograms; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “.C” refers to degrees Celsius; “mm Hg” refersto millimeters of mercury; “μL” refers to microliters; “μg” refers tomicrograms; and “μM” refers to micromolar.

EXAMPLE 22

Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid,N-methoxy-N-methylamide

Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) in toluene(80 mL) and add, by dropwise addition over 5 minutes, thionyl chloride(15 mL, 206 mmol). Stir at room temperature overnight, add additionalthionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1 hour. Removeexcess thionyl chloride by azeotropic distillation with toluene (40 mL).Add toluene (20 mL) to the reaction mixture along with a solution ofpotassium carbonate (28.0 g, 203 mmol) in water (40 mL). Add, bydropwise addition, a solution of N,O-dimethylhydroxylamine hydrochloride(8.9 g, 91.2 mmol) in water (20 mL) without cooling and stir for 2hours. Add tert-butylmethyl ether (75 mL) following by slow addition ofaqueous HCl (2N, 75 mL) with vigorous stirring. Separate the organiclayer and wash with aqueous HCl (2N, 75 mL), saturated sodium hydrogencarbonate (25 mL) and brine (50 mL). Dry the organic layer over(Na₂SO₄), filter, evaporate the filtrate in vacuo and purify by vacuumdistillation to give 2-methyl-2-phenyl-propionic acid,N-methoxy-N-methylamide (18.0 g, 95%); bp 91-103° C./5 mm Hg.

MS (CI, CH₄) m/e 208 (M⁺+1, 100), 119.

Slurry AlCl₃ (10.15 g, 76.1 mmol) and methylene chloride (45 mL) under anitrogen atmosphere at room temperature. Add 4-chlorobutyryl chloride(4.27 mL, 38.1 mmol), stir for 20 minutes and add, by dropwise additionover 10 minutes, a solution of 2-methyl-2-phenyl-propionic acid,N-methoxy-N-methylamide (6.58 g, 31.7 mmol) in methylene chloride (15mL). Stir at room temperature for 45 minutes, then heat at 30-35° C. for7 hours. Pour into ice water (150 mL) and separate the layers. Wash theaqueous layer with water (3×75 mL), combine the aqueous layers andextract with methylene chloride (2×75 mL). Combine the organic layersand dry (Na₂SO₄). Filter, evaporate the filtrate in vacuo and purify bysilica gel chromatography (3:1 hexane/ethyl acetate) give the titlecompound (6.19 g, 63%) as a light yellow oil.

MS (CI,CH₄) m/e 312 (M⁺+1), 276.

EXAMPLE 23

Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid,Dimethylamide

Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) in toluene(80 mL) and add, by dropwise addition over 5 minutes, thionyl chloride(15 mL, 206 mmol). Stir at room temperature overnight, add additionalthionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1 hour. Removeexcess thionyl chloride by azeotropic distillation with toluene (40 mL).Add toluene (20 mL) to the reaction mixture along with a solution ofpotassium carbonate (28.0 g, 203 mmol) in water (40 mL). Add, bydropwise addition, a 40% aqueous solution of dimethylamine hydrochloride(20 mL, 0.18 mol) without cooling and stir for 2 hours. Addtert-butylmethyl ether (75 mL) following by slow addition of aqueous HCl(2N, 75 mL) with vigorous stirring. Separate the organic layer and washwith aqueous HCl (2N, 75 mL), saturated sodium hydrogen carbonate (25mL) and brine (50 mL). Dry the organic layer over (Na₂SO₄), filter,evaporate the filtrate in vacuo and purify by crystallization to give2-methyl-2-phenyl-propionic acid, dimethylamide (15.35 g, 88%) as awhite solid; mp 57-59° C.

Anal. Calcd for C₁₂H₁₇NO: C, 75.35; H, 8.96; N, 7.32; Found: C, 75.12;H, 8.86; N, 7.26.

Add AlCl₃ (1.12 g, 8.40 mmol) to carbon tetrachloride (6 mL) under anitrogen atmosphere at room temperature. Add 4-chlorobutyryl chloride(0.49 mL, 4.37 mmol), stir for 15 minutes and add, by dropwise additionover 3 minutes, a solution of 2-methyl-2-phenyl-propionic acid,dimethylamide (0.64 g, 3.36 mmol) in carbon tetrachloride (6 mL). Stirat room temperature for 17 hours, dilute with methylene chloride (10mL), pour into ice water (50 mL) and separate the layers. Wash theaqueous layer with methylene chloride (2×70 mL), 5% aqueous sodiumhydrogen carbonate, combine the organic layers and dry (Na₂SO₄). Filter,evaporate the filtrate invacuo and purify by silica gel chromatography(5:2 hexane/ethyl acetate) to give the title compound (0.72 g, 72%) as alight yellow oil.

EXAMPLE 24

Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic AcidPyrrolidineamide

Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) in toluene(80 mL) and add, by dropwise addition over 5 minutes, thionyl chloride(15 mL, 206 mmol). Stir at room temperature overnight, add additionalthionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1 hour. Removeexcess thionyl chloride by azeotropic distillation with toluene (40 mL).Add tolune (20 mL) to the reaction mixture along with a solution ofpotassium carbonate (28.0 g, 203 mmol) in water (40 mL). Add, bydropwise addition, pyrrolidine (7.61 mL, 91 mmol) without cooling andstir for 2 hours. Add tert-butylmethyl ether (75 mL) following by slowaddition of aqueous HCl (2N, 75 mL) with vigorous stirring. Separate theorganic layer and wash with aqueous HCl (2N, 75 mL), saturated sodiumhydrogen carbonate (25 mL) and brine (50 mL). Dry the organic layer over(Na₂SO₄), filter, evaporate the filtrate in vacuo and purify bycrystallization to give 2-methyl-2-phenyl-propionic acid,pyrrolidineamide (18.28 g, 92%) as a solid; mp 96-97° C.

Anal. Calcd for C₁₄H₁₉NO: C, 77.38; H, 8.81; N, 6.45; Found: C, 77.21;H, 8.70; N, 6.41.

Add AlCl₃ (8.31 g, 62.3 mmol) to carbon tetrachloride (65 mL) under anitrogen atmosphere at room temperature. Add 4-chlorobutyryl chloride(03.5 mL, 31.2 mmol), stir for 15 minutes and add, by dropwise additionover 15 minutes, a solution of 2-methyl-2-phenyl-propionic acid,pyrrolidineamide (5.64 g, -26.0 mmol) in carbon tetrachloride (60 mL).Stir at room temperature for 17 hours, pour into ice water (100 mL) andseparate the layers. Wash the aqueous layer with methylene chloride(2×70 mL), 5% aqueous sodium hydrogen carbonate, combine the organiclayers and dry (Na₂SO₄). Filter, evaporate the filtrate in vacuo andpurify by silica gel chromatography (5:2 hexane/ethyl acetate) to givethe title compound (6.55 g, 78%) as a light yellow oil.

EXAMPLE 25

Step l: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic Acid,N-methoxy-N-methylamide

Add potassium hydroxide (13 g) to2-[4-(4-chloro-butyryl-phenyl]-2-methyl-propionamide,N-methoxy-N-methylamide (96.6 mmol) and stir at room temperature for 40minutes, filter and wash the filtercake with ethanol. Evaporate theethanol in vacuo, dissolve in methylene chloride (100 mL), wash withwater (50 mL), 5% sodium hydrogen carbonate (50 mL) and water (50 mL).Evaporate the solvent in vacuo, removing water with toluene azeotrooe.Purify the product by distillation followed by recrystallization(heptane) to give the title compound (7.4 g).

The following compounds can be prepared by procedures depicted in SchemeG:

(4-cyclopropanecarbonyl-phenyl)-acetic acid, N-methoxy-N-methylamide:

(4-cyclopropanecarbonyl-phenyl)-acetic acid, dimethylamide;

(4-cyclopropanecarbonyl-phenyl)-acetic acid, pyrrolidineamide;

2-(4-Cyclopropanecarbonyl-phenyl)-proprionic acid,N-methoxy-N-methylamide;

2-(4-Cyclopropanecarbonyl-phenyl)-proprionic acid, dimethylamide;

2-(4-Cyclopropanecarbonyl-phenyl)-proprionic acid, pyrrolidineamide;

2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-proprionic acid,N-methoxy-N-methylamide;

2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-proprionic acid,dimethylamide;

2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-proprionic aced,pyrrolidineamide;

[4-(4-Chloro-butyryl)-phenyl]-acetic acid, N-methoxy-N-methylamide;

[4-(4-Chloro-butyryl)-phenyl]-acetic acid, dimethylamide:

[4-(4-Chloro-butyryl)-phenyl]-acetic acid, pyrroldineamide;

2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid, N-methoxy-N-methylamide;

2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid, dimethylamide;

2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid, pyrroldineamide;

2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid,N-methoxy-N-methylamide;

2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid. dimethylamide;

2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid,pyrroldineamide;

The novel intermediates of formula (II), formula (III), formula (IV),formula (V), formula (VI) and formula (VII) wherein R₅ is COOH, COOalkylor CONR₆R₇ may be prepared as described in Scheme H. In Scheme H, allsubstituents are as previously defined unless otherwise indicated.

Scheme H provides various general synthetic procedures for preparing thenovel intermediates of formula (II), formula (III), formula (IV),formula (V), formula (VI) and formula (VII) wherein R₅ is COOH, COOalkylor CONR₆R₇.

In step a, the nitrile functionality of the appropriateω-halo-cyanocumylketone compound of structure (19) is converted to thecorresponding ester by reaction with an appropriate C₁ to C₆ alcohol togive the corresponding ω′-halo-α′-keto-α,α-dimethylphenylacetic acidester compound of structure (31).

For example, the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid estercompound of structure (31) may be prepared by reacting an appropriateω-halo-cyanocumylketone compound of structure (19) with an appropriateC₁-C₆ alcohol in the presence of a suitable anhydrous acid followed bytreatment with water. Examples of appropriate alcohols are methanol,ethanol, propanol, and the like, with methanol being preferred. Examplesof appropriate acids are hydrogen chloride and hydrogen bromide, withhydrogen chloride being preferred. The reaction time varies from about ½hour to 48 hours, preferably 3 to 5 hours and the reaction temperaturevaries from about −20° C. to room temperature, preferably −10° C. to 0°C. The ω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound ofstructure (28) is recovered from the reaction zone by evaporation of thesolvent followed by extraction as is known in the art. Theω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound ofstructure (31) may be purified by procedures well known in the art, suchas chromatography.

In step b, the nitrile functionality of the appropriateω-halo-cyanocumylketone compound of structure (19) is converted to thecorresponding amide to give the ω′-halo-α′-keto-α′-dimethylphenylaceticacid amide compound of structure (40) wherein R₆ and R₇ are bothhydrogen.

For example, hydrolysis may be achieved by using a suitable acid, suchas concentrated hydrochloric acid as is known in the art.

In step c, the carboxy ester functionality of the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound ofstructure (31) is hydrolyzed to give the correspondingω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure(46).

For example, hydrolysis may be achieved by using a suitablenon-nucleophilic base, such as sodium methoxide in methanol as is knownin the art. Other methods known in the art for ester cleavage includepotassium carbonate in methanol, methanolic ammonia, potassiumcarbonate, potassium hydroxide, calcium hydroxide, sodium hydroxide,magnesium hydroxide, sodium hydroxide/pyridine in methanol, potassiumcyanide in ethanol and sodium hydroxide in aqueous alcohols, withpotassium hydroxide being preferred. The reaction is typically carriedout in an aqueous lower alcohol solvent, such as methanol, ethanol,isopropyl alcohol, n-butanol, 2-ethoxyethanol or ethylene glycol orpyridine, at temperatures ranging from room temperature to the refluxtemperature of the solvent, and the reaction time varies from about ½hour to 100 hours.

In step d, the carboxy functionality of the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)may be esterified by techniques and procedures well known andappreciated by one of ordinary skill in the art to give thecorresponding ω′-halo-α′-keto-α,α-dimethylphenylacetic acid estercompound of structure (31).

For example, one such method involves reacting an appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)with an excess of an appropriate C₁-C₆ alcohol which is straight orbranched in the presence of a small amount of mineral acid, such ashydrochloric acid or sulfuric acid, hydrochloric acid being preferred,at reflux. Another suitable method involves reacting an appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)with an excess of diazomethane in a suitable solvent such as ether atroom temperature to give the methyl ester. In addition, theω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound ofstructure (28) may also be prepared by reacting an appropriateω′-halo-α′-keto-α,α-di-methylphenylacetic acid compound of structure(46) with an excess of 2,2-dimethoxypropane in a suitable solvent suchas methanol at 0° C. to room temperature to give the methyl ester.Another suitable method involves first reacting an appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)with thionyl chloride in a suitable solvent such as methylene chlorideto give an intermediate acid chloride, followed by addition of asuitable C₁ to C₆ alcohol which is straight or branched. Anothersuitable method involves the alkylation of the carboxylate anion with anappropriate electrophile, such as dimethyl sulfate or ethyl bromide, togive the corresponding ω′-halo-α′-keto-α,α-dimethylphenylacetic acidester compound of structure (31). Such methods are well known in the artand are described in J. Org. Chem., 29, 2490-2491 (1964).

Alternatively, step k and step d may be combined and theω′-halo-α′-keto-α′-dimethylphenylacetic acid ester compound of structure(34) wherein n=3 may be prepared from the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid compound of structure(50).

Alternatively, step p, step k and step d may be combined and theω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound ofstructure (31) wherein n=3 may be prepared from the correspondingcyclopropyl cyanocumylketone compound of structure (20).

In step e, the nitrile functionality of the appropriateω-halo-cyanocumylketone compound of structure (19) is converted to thecorresponding carboxy to give theω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure(46).

For example, hydrolysis may be achieved by using a suitable acid, suchas concentrated hydrochloric acid as is known in the art.

In step f, the amide functionality of the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid amide compound ofstructure (40) is converted to the corresponding acid by acid hydrolysisas is known in the art to give the correspondingω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure(46).

For example, hydrolysis may be achieved by using a suitablenon-nucleophilic base, such as sodium methoxide in methanol as is knownin the art. Other methods known in the art for ester cleavage includepotassium carbonate in methanol, methanolic ammonia, potassiumcarbonate, potassium hydroxide, calcium hydroxide, sodium hydroxide,magnesium hydroxide, sodium hydroxide/pyridine in methanol, potassiumcyanide in ethanoland sodium hydroxide in aqueous alcohols, withpotassium hydroxide being preferred. The reaction is typically carriedout in an aqueous lower alcohol solvent, such as methanol, ethanol,isopropyl alcohol, n-butanol, 2-ethoxyethanol or ethylene glycol orpyridine, at temperatures ranging from room temperature to the refluxtemperature of the solvent, and the reaction time varies from about ½hour to 100 hours.

In step g, the carboxy functionality of the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)may be amidated by techniques and procedures well known and appreciatedby one of ordinary skill in the art to give the correspondingω′-halo-α′-keto-α,α-di-methylphenylacetic acid amide compound ofstructure (40).

In step h, the α-halo functionality of the appropriateω-halo-halocumylketone compound of structure (10) is carboxylated togive the corresponding ω′-halo-α′-keto-α,α-dimethylphenylacetic acidcompound of structure (46).

For example, a solution of the appropriate ω-halo-halocumylketonecompound of structure (10) and a suitable catalyst, such astetraethylammonium bromide, in a suitable polar aprotic organic solvent,such as acetonitrile, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone ordimethylformamide, are placed in a jacketed glass cell and fitted withan expanded silver mesh cathode, magnesium anode and carbon dioxidedelivery tube. Rotation of the electrodes provides stirring, whileelectrical contact with the electrodes is made via spring loaded slidingcarbon brushes placed against the concentric metal shafts (insulatedfrom each other with a length of plastic tubing) onto which theelectrodes are mounted. Carbon dioxide is introduced into the cell atpressures of 1-10 atm, for a period of time ranging from 30 minutes to50 hours and at a temperature range of from −30° C. to 50° C. Thecorresponding ω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound ofstructure (46) is isolated, after acidification with a suitable mineralacid, such as hydrochloric acid, by extractive methods as are known inthe art.

It is preferred that the ω-halo functionality of the appropriateω-halo-halocumylketone compound of structure (10) for use in step h be aω-chloro.

Alternatively, the treatment of appropriate ω-halo-halocumylketonecompound of structure (10) with a transition metal catalyst such aspalladium, nickel or cobalt, optionally in the presence of a phosphinecatalysis using low to modest pressures of carbon monoxide as describedby Stahly et al. in U.S. Pat. No. 4,990,658, 1991 also provides thecorresponding ω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound ofstructure (46).

In step i, the appropriate the amide functionality of the appropriateω′-halo-α′-keto-α,α-di-methylphenylacetic acid amide compound ofstructure (40) is converted to the corresponding ester to give theω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound ofstructure (31).

For example, the appropriate ω′-halo-α′-keto-α,α-di-methylphenylaceticacid amide compound of structure (40) is reacted with an appropriatehydrogen halide in an appropriate organic solvent such as ethanol. Thereaction is typically conducted at a temperature range of from roomtemperature to reflux and for a period of time ranging from 5 minutes to1 hour. The ω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compoundof structure (31) is recovered from the reaction zone by extractivemethods as is known in the art.

In step j, the appropriate ω′-halo-α′-keto-α,α-dimethylphenylacetic acidcompound of structure (46) wherein n=3 is ring-closed to give thecorresponding cyclopropylketo-α,α-dimethylphenylacetic acid compound ofstructure (47) as described previously in Scheme A, step k.

In step k, the appropriate cyclopropylketo-α,α-dimethylphenylacetic acidcompound of structure (47) is ring-opened to give the correspondingω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)wherein n=3 as described previously in Scheme A, step j.

In step 1, the nitrile functionality of the appropriate cyclopropylcyanocumylketone compound of structure (20) is converted to thecorresponding ester by reaction with an appropriate C₁ to C₆ alcohol togive the cyclopropylketo-α,α-dimethylphenylacetic acid ester compound ofstructure (32) as described previously in step a.

In step m, the nitrile functionality of the appropriate cyclopropylcyanocumylketone compound of structure (20) is converted to thecorresponding amide to give theω′-halo-α′-keto-α,α-di-methylphenylacetic acid amide compound ofstructure (41) wherein R₆ and R₇ are both hydrogen as describedpreviously in step b.

In step n, the carboxy ester functionality of the appropriatecyclopropylketo-α,α-dimethylphenylacetic acid ester compound ofstructure (32) is hydrolyzed to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)as described previously in step c.

In step o, the carboxy functionality of the appropriatecyclopropylketo-α,α-dimethylphenylatetic acid compound of structure (47)may be esterified by techniques and procedures well known andappreciated by one of ordinary skill in the art to give thecorresponding cyclopropylketo-α,α-dimethylphenylacetic acid estercompound of structure (32) as described previously in step d.

In step p, the nitrile functionality of the appropriate cyclopropylcyanocumylketone compound of structure (20) is converted to thecorresponding carboxy to give thecyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)as described previously in step e.

In step q, the amide functionality of the appropriatecyclopropylketo-α,α-dimethylphenylacetic acid amide compound ofstructure (41) is converted to the corresponding acid by acid hydrolysisas is known in the art to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)as described previously in step f.

In addition, step q and step k may be combined and theω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)wherein n=3 may be prepared from the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid amide compound ofstructure (41) as described previously in Scheme A, step j.

In step r, the carboxy functionality of the appropriatecyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)may be amidated by techniques and procedures well known and appreciatedby one of ordinary skill in the art to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid amide compound ofstructure (41) as described previously in step g.

In step s, the α-halo functionality of the appropriate cyclopropylhalocumylketone compound of structure (11) is carboxylated to give thecorresponding cyclopropylketo-α,α-dimethylphenylacetic acid compound ofstructure (47) as described previously in step h.

In step t, the appropriate the amide functionality of the appropriatecyclopropylketo-α,α-dimethylphenylacetic acid amide compound ofstructure (41) is converted to the corresponding ester to give thecyclopropylketo-α,α-dimethylphenylacetic acid ester compound ofstructure (32) as described previously in step i.

In step u, the nitrile functionality of the appropriateω-halo-cyanoethylphenylketone compound of structure (21) is converted tothe corresponding ester by reaction with an appropriate C₁ to C₆ alcoholto give the ω′-halo-α′-keto-α-methylphenylacetic acid ester compound ofstructure (33) as described previously in step a.

In step v, the nitrile functionality of the appropriateω-halo-cyanoethylphenylketone compound of structure (21) is converted tothe corresponding amide to give the ω′-halo-α′-keto-α-methylphenylaceticacid amide compound of structure (42) wherein R₆ and R₇ are bothhydrogen as described previously in step b.

In step w, the carboxy ester functionality of the appropriateω′-halo-α′-keto-α-methylphenylacetic acid ester compound of structure(33) is hydrolyzed to give the correspondingω-halo-α′-keto-α-methylphenylacetic acid compound of structure (48) asdescribed previously-in step c.

In step x, the carboxy functionality of the appropriateω′-halo-α′-keto-α-methylphenylacetic acid compound of structure (48) maybe esterified by techniques and procedures well known and appreciated byone of ordinary skill in the art to give the correspondingω′-halo-α′-keto-α-methylphenylacetic acid ester compound of structure(33) as described previously in step d.

Alternatively, step ee and step x may be combined and theω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound ofstructure (33) wherein n=3 may be prepared from the correspondingcyclopropylketo-α-methylphenylacetic acid compound of structure (49) asdescribed previously in step d.

Alternatively, step jj, step ee and step x may be combined and theω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound ofstructure (33) wherein n=3 may be prepared from the correspondingcyclopropyl cyanoethylphenylketone compound of structure (23) asdescribed previously in step d.

In step y, the nitrile functionality of the appropriateω-halo-cyanoethylphenylketone compound of structure (21) is converted tothe corresponding carboxy to give theω′-halo-α′-keto-α-methylphenylacetic acid compound of structure (48) asdescribed previously in step e.

In step z, the amide functionality of the appropriateω′-halo-α′-keto-α-methylphenylacetic acid amide compound of structure(42) is converted to the corresponding acid by acid hydrolysis as isknown in the art to give the ω′-halo-α′-keto-α-methylphenylacetic acidcompound of structure (48) as described previously in step f.

In step aa, the carboxy functionality of the appropriateω′-halo-α′-keto-α-methylphenylacetic acid compound of structure (48) maybe amidated by techniques and procedures well known and appreciated byone of ordinary skill in the art to give the correspondingω′-halo-α′-keto-α-methylphenylacetic acid amide compound of structure(42) as described previously in step g.

In step bb, the α-halo functionality of the appropriateω-halo-haloethylphenylketone compound of structure (12) is carboxylatedto give the corresponding ω′-halo-α′-keto-α-methylphenylacetic acidcompound of structure (48) as described previously in step h.

In step cc, the appropriate the amide functionality of the appropriateω′-halo-α′-keto-α-methylphenylacetic acid amide compound of structure(42) is converted to the corresponding ester to give theω′-halo-α′-keto-α-methylphenylacetic acid ester compound of structure(33) as described previously in step i.

In step dd, the appropriate ω′-halo-α′-keto-α-methylphenylacetic acidcompound of structure (48) wherein n=3 is ring-closed to give thecorresponding cyclopropylketo-α-methylphenylacetic acid compound ofstructure (49) as described previously in Scheme A, step k.

In step ee, the appropriate cyclopropylketo-α-methylphenylacetic acidcompound of structure (49) is ring-opened to give the correspondingω′-halo-α′-keto-α-methylphenylacetic acid compound of structure (48)wherein n=3 as described previously in Scheme A, step j.

In step ff, the nitrile functionality of the appropriate cyclopropylcyanoethylphenylketone compound of structure (23) is converted to thecorresponding ester by reaction with an appropriate C₁ to C₆ alcohol togive the cyclopropylketo-α-methylphenylacetic acid ester compound ofstructure (35) as described previously in step a.

In step gg, the nitrile functionality of the -appropriate cyclopropylcyanoethylphenylketone compound of structure (23) is converted to thecorresponding amide to give the cyclopropylketo-α-methylphenylaceticacid amide compound of structure (44) wherein R₆ and R₇ are bothhydrogen as described previously in step b.

In step hh, the carboxy ester functionality of the appropriatecyclopropylketo-α-methylphenylacetic acid ester compound of structure(35) is hydrolyzed to give the correspondingcyclopropylketo-α-methylphenylacetic acid compound of structure (49) asdescribed previously in step c.

In step ii, the carboxy functionality of the appropriatecyclopropylketo-α-methylphenylacetic acid compound of structure (49) maybe esterified by techniques and procedures well known and appreciated byone of ordinary skill in the art to give the correspondingcyclopropylketo-α-methylphenylacetic acid ester compound of structure(35) as described previously in step d.

In step jj, the nitrile functionality of the appropriate cyclopropylcyanoethylphenylketone compound of structure (23) is converted to thecorresponding carboxy to give the cyclopropylketo-α-methylphenylaceticacid compound of structure (49) as described previously in step e.

In step kk, the amide functionality of the appropriatecyclopropylketo-α-methylphenylacetic acid amide compound of structure(44) is converted to the corresponding acid by acid hydrolysis as isknown in the art to give the correspondingcyclopropylketo-α-methylphenylacetic acid compound of structure (49) asdescribed previously in step f.

In addition, step kk and step ee may be combined and theω′-halo-α′-keto-α-methylphenylacetic acid compound of structure (48)wherein n=3 may be prepared from the correspondingcyclopropylketo-α-methylphenylacetic acid amide compound of structure(44) as described previously in Scheme A, step j.

In step ll, the carboxy functionality of the appropriatecyclopropylketo-α-methylphenylacetic acid compound of structure (49) maybe amidated by techniques and procedures well known and appreciated byone of ordinary skill in the art to give the correspondingcyclopropylketo-α-methylphenylacetic acid amide compound of structure(44) as described previously in step g.

In step mm, the α-halo functionality of the appropriate cyclopropylhaloethylphenylketone compound of structure (14) is carboxylated to givethe corresponding cyclopropylketo-α-methylphenylacetic acid compound ofstructure (49) as described previously in step h.

In step nn, the appropriate the amide functionality of the appropriateω′-halo-α′-keto-α-methylphenylacetic acid amide compound of structure(42) is converted to the corresponding ester to give theω′-halo-α′-keto-α-methylphenylacetic acid ester compound of structure(33) as described previously in step i.

In step oo, the nitrile functionality of the appropriate ω-halocyanotolylketone compound of structure (22) is converted to thecorresponding ester by reaction with an appropriate C₁ to C₆ alcohol togive the ω′-halo-α′-keto-phenylacetic acid ester compound of structure(34) as described previously in step a.

In step pp, the nitrile functionality of the appropriate ω-halocyanotolylketone compound of structure (22) is converted to thecorresponding amide to give the ω′-halo-α′-keto-phenylacetic acid amidecompound of structure (43) wherein R₆ and R₇ are both hydrogen asdescribed previously in step b.

In step qq, the carboxy ester functionality of the appropriateω′-halo-α′-keto-phenylacetic acid ester compound of structure (34) ishydrolyzed to give the corresponding ω′-halo-α′-keto-methylphenylaceticacid compound of structure (50) as described previously in step c.

In step rr, the carboxy functionality of the appropriateω′-halo-α′-keto-methylphenylacetic acid compound of structure (50) maybe esterified by techniques and procedures well known and appreciated byone of ordinary skill in the art to give the correspondingω′-halo-α′-keto-phenylacetic acid ester compound of structure (34) asdescribed previously in step d.

Alternatively, step yy and step rr may be combined and theω′-halo-α′-keto-phenylacetic acid ester compound of structure (34)wherein n=3 may be prepared from the correspondingω′-halo-α′-keto-methylphenylacetic acid compound of structure (50) asdescribed previously in step d.

Alternatively, step ddd, step yy and step rr may be combined theω′-halo-α′-keto-phenylacetic acid ester compound of structure (34)wherein n=3 may be prepared from the corresponding cyclopropylcyanotolylketone compound of structure (24) as described previously instep d.

In step ss, the nitrile functionality of the appropriate ω-halocyanotolylketone compound of structure (22) is converted to thecorresponding carboxy to give the ω′-halo-α′-keto-methylphenylaceticacid compound of structure (50) as described previously in step e.

In step tt, the amide functionality of the appropriateω′-halo-α′-keto-phenylacetic acid amide compound of structure (43) isconverted to the corresponding acid by acid hydrolysis as is known inthe art to give the ω′-halo-α′-keto-methylphenylacetic acid compound ofstructure (50) as described previously in step f.

In step uu, the carboxy functionality of the appropriateω′-halo-α′-keto-methylphenylacetic acid compound of structure (50) maybe amidated by techniques and procedures well known and appreciated byone of ordinary skill in the art to give the correspondingω′-halo-α′-keto-phenylacetic acid amide compound of structure (43) asdescribed previously in step g.

In step vv, the α-halo functionality of the appropriate ω-halohalotolylketone compound of structure (13) is carboxylated to give thecorresponding ω′-halo-α′-keto-methylphenylacetic acid compound ofstructure (50) as described previously in step h.

In step ww, the appropriate the amide functionality of the appropriateω′-halo-α′-keto-phenylacetic acid amide compound of structure (43) isconverted to the corresponding ester to give theω′-halo-α′-keto-phenylacetic acid ester compound of structure (34) asdescribed previously in step i.

In step xx, the appropriate ω′-halo-α′-keto-methylphenylacetic acidcompound of structure (50) wherein n=3 is ring-closed to give thecorresponding cyclopropylketo-phenylacetic acid compound of structure(51) as described previously in Scheme A, step k.

In step yy, the appropriate cyclopropylketo-phenylacetic acid compoundof structure (51) is ring-opened to give the correspondingω′-halo-α′-keto-methylphenylacetic acid compound of structure (50)wherein n=3 as described previously in Scheme A, step j.

In step zz, the nitrile functionality of the appropriate cyclopropylcyanotolylketone compound of structure (24) is converted to thecorresponding ester by reaction with an appropriate C₁ to C₆ alcohol togive the cyclopropylketo-phenylacetic acid ester compound of structure(36) as described previously in step a.

In step aaa, the nitrile functionality of the appropriate cyclopropylcyanotolylketone compound of structure (24) is converted to thecorresponding amide to give the cyclopropylketo-phenylacetic acid amidecompound of structure (45) wherein R₆ and R₇ are both hydrogen asdescribed previously in step b.

In step bbb, the carboxy ester functionality of the appropriatecyclopropylketo-phenylacetic acid ester compound of structure (36) ishydrolyzed to give the corresponding cyclopropylketo-phenylacetic acidcompound of structure (51) as described previously in step c.

In step ccc, the carboxy functionality of the appropriatecyclopropylketo-phenylacetic acid compound of structure (51) may beesterified by techniques and procedures well known and appreciated byone of ordinary skill in the art to give the correspondingcyclopropylketo-phenylacetic acid ester compound of structure (36) asdescribed previously in step d.

In step ddd, the nitrile functionality of the appropriate cyclopropylcyanotolylketone compound of structure (24) is converted to thecorresponding carboxy to give the cyclopropylketo-phenylacetic acidcompound of structure (51) as described previously in step e.

In step eee, the amide functionality of the appropriatecyclopropylketo-phenylacetic acid amide compound of structure (45) isconverted to the corresponding acid by acid hydrolysis as is known inthe art to give the corresponding cyclopropylketo-phenylacetic acidcompound of structure (51) as described previously in step f.

In addition, step yy and step eee may be combined and theω′-halo-α′-keto-methylphenylacetic acid compound of structure (50)wherein n=3 may be prepared from the correspondingcyclopropylketo-phenylacetic acid amide compound of structure (45) asdescribed previously in Scheme A, step j.

In step fff, the carboxy functionality of the appropriatecyclopropylketo-phenylacetic acid compound of structure (51) may beamidated by techniques and procedures well known and appreciated by oneof ordinary skill in the art to give the correspondingcyclopropylketo-phenylacetic acid amide compound of structure (45) asdescribed previously in step g.

In step ggg, the α-halo functionality of the appropriate cyclopropylhalotolylketone of structure (15) is carboxylated to give thecorresponding cyclopropylketo-phenylacetic acid compound of structure(51) as described previously in step h.

In step hhh, the appropriate the amide functionality of the appropriatecyclopropylketo-phenylacetic acid amide compound of structure (45) isconverted to the corresponding ester to give thecyclopropylketo-phenylacetic acid ester compound of structure (36) asdescribed previously in step i.

Starting materials for use in Scheme H are readily available to one ofordinary skill in the art.

The following examples present typical syntheses as A described inScheme H. These examples are understood to be illustrative only and arenot intended to limit the scope of the present invention in any way. Asused herein, the following terms have the indicated meanings: “g” refersto grams; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 26

Step a: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid, MethylEster

Place anhydrous methanol (5 mL) under argon, cool to 0° C. and addhydrogen chloride until saturated. Add2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionitrile (103 mg, 4.12mmol), remove the ice bath and stir for 5 hours at room temperature.Allow to stand at −10° C. overnight, and stir an additional 3 hours atroom temperature. Pour into cracked ice (20 g) and allow to stand for 5minutes.

Evaporate the solvent in vacuo to ½ volume, dilute with water andextract with methylene chloride (3×). Combine the organic layers, washwith saturated sodium hydrogen carbonate and brine. Dry (MgSO₄), filterand evaporate the solvent in vacuo. Extract the residue into hot hexane(12 mL), filter hot and evaporate the solvent in vacuo to give the titlecompound as a colorless oil (97 mg, 83%).

EXAMPLE 27

Step d: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid, EthylEster

Add anhydrous hydrogen chloride gas (18.0 g) to anhydrous ethanol DB(210 g) by purging the solution. Add this hot solution (60° C.) to asolution of 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid (31g, 115.6 mmol) and reflux under a nitrogen atmosphere for 2.5 hours.Evaporate the solvent in vacuo, dissolve the residue in methylenechloride (150 mL) and wash with water (2×100 mL). Dry (MgSO₄), filterthrough silica gel, washing the gel with methylene chloride (250 mL).Combine the organic washings and evaporate the solvent in vacuo to givethe title compound as a colorless oil (33.3 g, 97%).

¹H NMR (300 MHz, CDCl₃) δ 7.96 (d, J=8.3 Hz, 2H), 7.45 (d, J=8.3 Hz,2H), 4.15 (q, J=7.1 Hz, 2H), 3.70 (t, J=6.6 Hz, 2H), 3.19 (t, J=6.8 Hz,2H), 2.25 (p, J=6.6 Hz, 2H), 1.61 (s, 6H), 1.20 (q, J=7.1 Hz, 3H); ¹³CNMR (75 MHz, CDCl₃) δ 198.4, 176.0, 150.3, 135.1, 128.1, 126.0, 61.0,46.8, 44.6, 35.2, 26.7, 26.3, 14.0; IR (neat) 2978, 1728, 1686, 1606,1254, 1231, 1148, 1097 cm⁻¹.

Anal. Calcd for C₁₆H₂₁O₃Cl: C, 64.75; H, 7.13; Found: C, 64.24; H, 7.18.

EXAMPLE 28

Step d: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid, MethylEster

Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid (6.2 g,23.1 mmol) in hot methanolic solution of anhydrous hydrogen chloride (42mL of a methanol containing 3.2 g of anhydrous hydrogen chloride).Reflux for 42 minutes, evaporate the solvent in vacuo, dissolve theresidue in methylene chloride and wash with water. Dry (MgSO₄), filterthrough silica gel, washing the gel with methylene chloride. Combine theorganic washings and evaporate the solvent in vacuo to give the titlecompound as a clear oil (6.21 g, 94%).

1H NMR (30 MHz, CDCl₃) δ 7.95 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.5 Hz, 2H),3.66 (s, 3H), 3.67 (t, J=6.6 Hz, 2H), 3.17 (t, J=6.6 Hz, 2H), 2.30 (p,J=6.6 Hz, 2H), 1.61 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 198.0, 176.2,149,8, 135.0, 128.0, 125.8, 52.4, 46.9, 44.7, 35.3, 26.8, 26.5.

Anal. Calcd for C₁₅H₁₉O₃Cl: C, 63.72; H, 6.77; Found: C, 63.50; H, 6.67.

EXAMPLE 29

Step d: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid, MethylEster

Mix 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid (10.0 g,37.3 mmol) and anhydrous potassium carbonate (3.5 g, 25.3 mmol). Heat to40° C. in acetonitrile (100 mL) and stir under a nitrogen atmosphere.Add dimethyl sulfate (13.3 g, 105 mmol) and reflux for 45 minutes.Evaporate the solvent in vacuo, dissolve the residue in ethyl acetate(50 mL) and wash with water (4×50 mL). Dry (MgSO₄), filter throughsilica gel and evaporate the solvent in vacuo to give the title compound(6.4 g, 89%).

EXAMPLE 30

Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid

Fit a jacketed glass cell of about 6 L capacity with a rotating expandedsilver mesh cathode/magnesium anode assembly, a carbon dioxide deliverytube, and a stainless steel thermocouple. Load the cell withacetonitrile (5.8 L) and tetraethylammonium bromide (26 g). Sparge withcarbon dioxide and cool in cooling bath. When the contents of the cellreach −10° C., add hydrogen chloride remediated1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one and1-[4-(1-chloro-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (424.9 g,53.5 mole % bromo and 20.4 mole % chloro by HPLC analysis, 1087 mmoltotal active tertiary benzylic halide) and perform electrolysis at acontrolled current of 8 amps (20 mA cm⁻²) for 6 hours. Drain thecontents, acidify with chilled aqueous 6M hydrochloric acid, extract,evaporate the solvent in vacuo and recrystallize to give the titlecompound (186 g, 64%); 78.5-80.3° C.

¹H NMR (300 MHz, CDCl₃) δ 10.5 (br s, 2H), 7.96 (d, J=8.2 Hz, 2E), 7.50(d, J=8.2 Hz, 2H), 3.67 (t, J=6.8 Hz, 2E), 3.17 (t, J=6.8 Hz, 2H), 2.22(m, J=6.7 Hz, 2H), 1.63 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 198.2, 181.9,149.0, 135.2, 128.1, 126.1, 46.7, 44.7, 35.3, 26.9, 26.7; MS (CIMS(Methane)) 271 (3), 269 (11), 233 (100), 187 (75).

Anal. Calcd for C₁₄H₁₇O₃Cl: C, 62.57; H, 6.38; Found: C, 63.10; H, 6.59.

EXAMPLE 31

Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid

Fit a jacketed glass cell of about 50 mL capacity with an expandedsilver mesh cathode (14 cm² geometric area), a roughly concentricmagnesium sacrificial anode, a tube to deliver carbon dioxide gas and amagnetic stir bar. Add a solution of hydrogen chloride remediated1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one and1-[4-(1-chloro-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (2.79 g, 89mole %, 3:1 ratio of tertiary benzylic bromide to tertiary benzylicchloride by NMR, approximately 8.6 mmol total active tertiary benzylichalide) in acetonitrile (45 mL) and tetraethylammonium bromide (0.19 g).Close the cell and cool to −10° C. with a continuous carbon dioxidesparge for 169 minutes at an average current density of 13 mA cm⁻². Warmto contents of the cell to ambient temperature, drain the contents,acidify with chilled aqueous 6M hydrochloric acid, extract and evaporatethe solvent in vacuo to give the title compound (1.53 g, 66%).

EXAMPLE 32

Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid

Fit a jacketed glass cell of 50 mL capacity with an expanded silver meshcathode (14 cm2 geometric area), a roughly concentric magnesiumsacrificial anode, a tube to deliver carbon dioxide gas, and a magneticstir bar. Cool the cell to −10° C. under carbon dioxide. Add a solutionof tetraethylammonium chloride (40 mL of a 0.02M solution indimethylformamide) and1-[4-(1-chloro-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (2.91 g, 85%pure by NMR, 9.81 mmol) and carry out electrolysis for 178 minutes at anaverage current density of 12.4 mA cm-2: the total charge passed isequal to 98% of the calculated theoretical two electron value. Warm thecontents of the cell to ambient temperature, drain the contents, acidifywith chilled aqueous 6M hydrochloric acid, extract and evaporate thesolvent in vacuo to give the title compound (1.89 g, 72%).

EXAMPLE 33

Step m: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionamide

Dissolve 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile (100mg) in aqueous ethanolic potassium hydroxide (2 mL) (prepared fromethanol (5 mL), water (5 mL) and solid potassium hydroxide (1.5 g). Stirovernight at room temperature, then heat at reflux for 6 hours. Cool andevaporate the solvent in vacuo to give the title compound.

EXAMPLE 34

Step t: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester

Dissolve 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionamide (100mg) in ethanol and bubble in hydrochloride gas for 5 minutes whilestirring. Reflux for 10 hours, distill off the ethanol and extract intoethyl acetate. Evaporate the solvent in vacuo to give the title compoundas an oil (50 mg).

EXAMPLE 35

Step k and Step q: 2-[4-(4-Bromo-butyryl)-phenyl]-2-methyl-propionicAcid

Treat2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-N-methyl-N-methoxy-propionamide(0.15 g, 0.53 mmol) with 48% HBr (1 mL) for 2 hours at 80° C. Cool toroom temperature, dilute with water (5 mL) and neutralize with aqueoussodium hydrogen carbonate until pH 7. Extract with methylene chloride(3×15 mL), dry (Na₂SO₄), filter and evaporate the solvent in vacuo.Purify by silica gel chromatography (3:1 hexane/ethyl acetate) to givethe title compound (0.15 g, 95%).

¹H NMR (CDCl₃) δ 7.97 (d, 2H), 7.51 (d, 2H), 3.53 (t, 2H), 3.16 (t, 2H),2.30 (quin, 2H), 1.60 (s, 6H); ¹³C NMR (CDCl₃) δ 198.4, 181.8, 149.5,131.0, 128.3, 126.3, 46.6, 36.5, 33.6, 26.9, 26.1; MS (CI) (M++H) 303(100), 315 (98), 233 (80).

EXAMPLE 36

Step p: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic Acid

Combine 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile (0.5 g)in 12.5% sodium hydroxide (20 mL) and ethanol (12.5 mL). Heat to refluxfor 21 hours, cool and remove the ethanol by vacuum distillation.Extract the residual aqueous suspension with methylene chloride (40 mL),acidify the aqueous phase with 20% HCl and extract with methylenechloride (2×40 mL). Combine the organic phases, dry (Na₂SO₄) andevaporate the solvent in vacuo to give the title compound as acrystalline solid (350mg, 70%); mp 83-85° C.

¹H NMR (CDCl₃) δ 7.50-8.00 (4H, d), 2.66 (1H, m), 1.62 (6H, s), 1.24(2H, m), 1.04 (2H, m).

The following compounds can be prepared by using the procedures depictedin Scheme H:

(4-Cyclopropanecarbonyl-phenyl)-acetic acid;

2-(4-Cyclopropanecarbonyl-phenyl)-propionic acid;

2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid;

[4-(4-Chloro-butyryl)-phenyl]-acetic acid;

2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid;

2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid;

(4-Cyclopropanecarbonyl-phenyl)-acetic acid, ethyl ester;

2-(4-Cyclopropanecarbonyl-phenyl)-propionic acid, ethyl ester;

[4-(4-Chloro-butyryl)-phenyl]-acetic acid, ethyl ester;

2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid, ethyl ester;

2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, ethyl ester;

(4-Cyclopropanecarbonyl-phenyl)-acetamide;

2-(4-Cyclopropanecarbonyl-phenyl)-propionamide;

[4-(4-Chloro-butyryl)-phenyl]-acetamide;

2-[4-(4-Chloro-butyryl)-phenyl]-propionamide; and

2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionamide.

In addition, the novel intermediate of formula (II) wherein R₅ is COOHmay be prepared as described in Scheme I. In Scheme I, all substituentsare as previously defined unless otherwise indicated.

Scheme I provides a general synthetic procedure for preparing the novelintermediate of formula (II) wherein R₅ is COOH.

In step a, the neophyl acetate of benzoate of structure (53) is acylatedwith an appropriate ω-halo compound of the structureHal-(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined to give the correspondingω′-halo-α′-keto-(2-methylpropanol)benzene acetate or benzoate compoundof structure (54) as described previously in Scheme A, step d.

The neophyl acetate of benzoate of structure (p53) is prepared byreacting a methallyl halide of structure

wherein Hal is Cl, Br or I with sodium acetate or sodium benzoate in asuitable organic solvent such as 1-methyl-2pyrrolidinone. The reactantsare heated at a temperature of approximately 100 to 130° C. and thecorresponding to give the methallyl acetate or benzoate of structure

wherein D′ is —C(═O)CH₃ or —C(═O)C₆H₅ which is collected bydistillation.

A benzene compound of structure

wherein A is defined above is then alkylated with the methylallylacetate or benzoate of structure

wherein D′ is —C(═O)CH₃ or —C(═O)C₆H₅ to give the neophyl acetate orbenzoate of structure (53) as described previously in Scheme A, step d.

In step a₂, the neophyl acetate or benzoate of structure (53) isacylated with an appropriate cyclopropyl compound of the structure

wherein B is as previously defined to give the corresponding cyclopropylneophyl acetate or benzoate of structure (55) as described previously inScheme A, step e.

In step b₁, the appropriate ω′-halo-α′-keto-(2-methylpropanol)benzeneacetate or benzoate compound of structure (54) wherein n=3 isring-closed to give the corresponding cyclopropyl neophyl acetate orbenzoate of structure (55) as described previously in Scheme A, step k.

In step b₂, the appropriate cyclopropyl neophyl acetate or benzoate ofstructure (55) is ring-opened to give the correspondingω′-halo-α′-keto-(2-methylpropanol)benzene acetate or benzoate compoundof structure (54) wherein n=3 as described previously in Scheme H, stepj.

In step c₁, the acetate or benzoate functionality of the appropriateω′-halo-α′-keto-(2-methylpropanol)benzene acetate or benzoate compoundof structure (54) is hydrolyzed with concentrated hydrochloric acid inethanol at reflux temperature for a period of time ranging from 1-10hours. The corresponding ω′-halo-α′-keto-(2-methylpropanol)benzenecompound of structure (56) is recovered from the reaction zone byextractive methods as is known in the art.

In step c₂, the appropriate ω′-halo-α′-keto-(2-methylpropanol)benzeneacetate or benzoate compound of structure (54) wherein n=3 is ringclosed and the acetate or benzoate functionality hydrolyzed with base togive the cyclopropyl neophyl alcohol compound of structure (57).

For example, the appropriate ω′-halo-α′-keto-(2-methylpropanol)benzeneacetate or benzoate compound of structure (54) wherein n=3 is reactedwith 40% aqeuous tetrabutylammonium hydroxide and 50% aqeuous sodiumhydroxide at reflux temperature for a period of time ranging from 5-72hours. The cyclopropyl neophyl alcohol compound of structure (57) may berecovered from the reaction zone by extractive methods as are known inthe art.

In step c₃, the acetate or benzoate functionality of the appropriatecyclopropyl neophyl acetate or benzoate of structure (55) is hydrolyzedto give the corresponding cyclopropyl neophyl alcohol of structure (57).

For example, the appropriate cyclopropyl neophyl acetate or benzoate ofstructure (55) is reacted with 50% aqueous sodium hydroxide at refluxtemperature for a period of time ranging from 5 minutes to 5 hours. Thecorresponding cyclopropyl neophyl alcohol of structure (57) is recoveredfrom the reaction zone by extractive methods as are known in the art.

In step d₁, the ω′-halo-α′-keto-(2-methylpropanol)benzene acetate orbenzoate compound of structure (54) is converted to the correspondingω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure(46).

For example, the appropriate cyclopropyl neophyl alcohol of structure(54) may be reacted with ruthenium chloride/sodium periodate in asuitable organic solvent such as acetonitrile and/or carbontetrachloride, ruthenium chloride/sodium hypochloride in a suitablesolvent such as acetic acid/water, potassium permanganate in a suitablesolvent such as acetic acid/water, fumic nitric acid in acetic acid orsodium nitrite/concentrated nitric acid in acetic acid. The reactantsare typically mixed stirred together at a temperature range of 10° C. to50° C. and for a period of time ranging from 30 minutes to 10 hours. Thecorresponding cyclopropylketo-α,α-dimethylphenylacetic acid compound ofstructure (46) is recovered from the reaction zone by extractive methodsas is known in the art.

In step d₂, the ω′-halo-α′-keto-(2-methylpropanol)benzene compound ofstructure (56) is converted to the correspondingω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure(46).

For example, the appropriate ω′-halo-α′-keto-(2-methylpropanol)benzenecompound of structure (56) may be oxidized with potassium permanganatein suitable acid solvent such as acetic acid. The reactants aretypically reacted at a temperature range of from about 0° C. to 5° C.for a period of time ranging from 30 minutes to 10 hours.

The corresponding ω′-halo-α′-keto-α,α-dimethylphenylacetic acid compoundof structure (46) is recovered from the reaction zone by extractivemethods as are known in the art and may be purified byrecrystallization. Other oxidizing reagents suitable for the oxidationof the appropriate ω′-halo-α′-keto-(2-methylpropanol)benzene compound ofstructure (56) to the correspondingω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)are nitric acid, chromium (IV) oxide, nitrogen dioxide, ruthenium (VIII)oxide, nickel peroxide, silver oxide, t-butyl chromate, xenic acid.

In step d₃, the hydroxymethyl functionality of the appropriateω′-halo-α′-keto-(2-methylpropanol)benzene compound of structure (56) isoxidized with a variety of oxidizing agents and methods to give thecorresponding ω′-halo-α′-keto-α,α-dimethylphenylacetaldehyde compound ofstructure (58).

One such method involves a procedure in which the hydroymethylfunctionality of the appropriateω′-halo-α′-keto-(2-methylpropanol)benzene compound of structure (56) isoxidized to the corresponding aldehyde functionality using, for example,Swern Oxidation conditions (dimethyl sulfoxide, oxalyl chloride andtriethylamine), as is known in the art. The Swern Oxidation is carriedout in a suitable aprotic organic solvent such as methylene chloride attemperatures ranging from about −78° C. to room temperature, and thereaction time varies from about ½ hours to 8 hours. Other suitablereagents for the oxidation of the hydroxyethyl functionality of theappropriate ω′-halo-α′-keto-(2-methylpropanol)benzene compound ofstructure (56) to the correspondingω′-halo-α′-keto-α,α-dimethylphenylacetaldehyde compound of structure(58) are Dess-Martin reagent, chromium (IV) oxide, nickel peroxide,sodium dichromate, potassium dichromate, t-butyl chromate, silver oxide,argentic picolinate, manganese dioxide, lead tetraacetate,dicyclohexylcarbodiimide, 2,3-dichloro-5,6-dicyanoquinone,tetrachloro-1,2-benzoquinone, 2,2,6,6-tetramethylpiperidinyl-l-oxy(TEMPO) or quinolinium chlorochromate.

In step d₄, the hydroxymethyl functionality of the appropriatecyclopropyl neophyl alcohol of structure (57) is oxidized to give thecorresponding cyclopropylketo-α,α-dimethylphenylacetaldehyde compound ofstructure (59) as described previously in step d₃.

In step d₅, the appropriate cyclopropyl neophyl alcohol of structure(57) is converted to the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)as described previously in step d₂.

In step d₆, the appropriate cyclopropyl neophyl acetate or benzoate ofstructure (55) is converted to the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)as described previously in step d₁.

In step e₁, the appropriate ω′-halo-α′-keto-(2-methylpropanol)benzenecompound of structure (56) wherein n=3 is ring-closed to give thecorresponding cyclopropyl neophyl alcohol of structure (57) as describedpreviously in Scheme H, step j.

In step e₂, the appropriate cyclopropyl neophyl alcohol of structure(57) is ring-opened to give the correspondingω′-halo-α′-keto-(2-methylpropanol)benzene compound of structure (56)wherein n=3 as described previously in Scheme H, step k.

In step f₁, the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetaldehyde compound of structure(58) wherein n=3 is ring-closed to give the correspondingcyclopropylketo-α,α-dimethylphenylacetaldehyde compound of structure(59) as described previously in Scheme H, step j.

In step f₂, the appropriatecyclopropylketo-α,α-dimethylphenylacetaldehyde compound of structure(59) is ring-opened to give the correspondingω′-halo-α′-keto-α,α-dimethylphenylacetaldehyde compound of structure(58) wherein n=3 as described previously in Scheme H, step k.

In step g₁, the aldehyde functionality of the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetaldehyde compound of structure(58) is oxidized to give the correspondingω-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46).

For example, the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetaldehyde compound of structure(58) is reacted with, for example, potassium permanganate. The potassiumpermanganate oxidation is carried out in a suitable acidic medium suchas hydrochloric acid/acetone at a temperature ranging from about 0° C.to room temperature and the reaction time varies from about ½ hour to 8hours. Other suitable reageants for the oxidation of theω′-halo-α′-keto-α,α-dimethylphenylacetaldehyde compound of structure(58) to the corresponding ω′-halo-α′-keto-α,α-dimethylphenylacetic acidcompound of structure (46) are chromium (IV) oxide, silver (I) oxide,silver oxide, argentic picolinate, peroxide, nitric acid,m-chloroperbenzoic acid and peracetic acid.

In step g₂, the aldehyde functionality of the appropriatecyclopropylketo-α,α-dimethylphenylacetaldehyde compound of structure(59) is oxidized to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)as described previously in step g₁.

Starting materials for use in Scheme I are readily available to one ofordinary skill in the art.

The following examples present typical syntheses as described in SchemeI. These examples are understood to be illustrative only and are notintended to limit the scope of the present invention in any way. As usedherein, the following terms have the indicated meanings: “g” refers tograms; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 37

Step a₁: 2-(4-(4-Chloro-1-oxo-butyl))-phenyl-2-methyl Propanyl Acetate

Mix 1-methyl-2-pyrrolidinone (400 mL , sodium acetate (205 g, 2.5 mol),stir at heat to 100° C. in a reaction flask which is fitted with adistillation head. Add, by dropwise addition, methylallyl chloride (181g, 2.0 mol) over 1 hour. Heat the pot to 120° C. for 30 minutes collectmethallyl acetate by distillation (193 g).

Mix methallyl acetate (228 g, 2.0 mol) and benzene (1 L) and cool to 5°C. Add aluminum chloride (266 g, 2.0 mol) over approximately 30 minuteswhile maintaining the temperature below 10° C. Add, in portions of 50 mLto 80 mL each, to a 5° C. mixture of aluminum chloride (15 g) in benzene(600 mL). After addition is complete, stir at 0-3° C. for ½ hour, pouronto ice (2 kg) and separate the organic layer. Wash with water (2×300mL), dry (Na₂SO₄), and distill to give neophyl acetate.

Dissolve neophyl acetate (150 g, 0.78 mol) in methylene chloride (390mL) and cool to 5° C. Add anhydrous aluminum chloride (104 g, 0.78 mol)at such a rate that the temperature is maintained below 10° C. Cool thereaction mixture to 5° C. Dissolve anhydrous aluminum chloride (122 g)in methylene chloride (390 mL) and cool to 5° C. Add 4-chlorobutyrylchloride (132 g, 0.94 mol) at such a rate that the temperature is keptbelow 10° C. Cool the reaction to 5° C. and add the neophylacetate-aluminum chloride solution in one portion and stir between −5°C. and 5° C. for 19 hours. Pour slowly over crushed ice (1.5 kg),separate the organic phase and wash with water (3×300 mL), cold aqueouspotassium carbonate (10%, 300 mL) and water (300 mL). Evaporate thesolvent in vacuo and filter to give the title compound as a light-brownoil (221.1 g, 95.6%).

¹H NMR (300 MHz, CDCl₃) δ 1.34 (6H, s), 1.95 (3H, s), 2.18 (2H, quent.),3.13 (2H, t), 3.65 (2H, t), 4.12 (2H, s), 7.43, 7.90 (2H each, d).

EXAMPLE 38

Step b₁: 2-(4-(1-Oxo-1-cyclopropanyl)-phenyl-2-methylpropanyl Acetate

Mix 2-(4-(4-chloro-1-oxo-butyl))-phenyl-2-methyl propanyl acetate (37.0g, 0.125 mol), tetrabutylammonium hydroxide (8.1 g of a 40% aqueoussolution), methylene chloride (300 mL) and 50% sodium hydroxide (40 mL).Stir vigorously at room temperature for 4 hours, add water (100 mL) andseparate the organic layer. Wash with water (2×100 mL), dry (MgSO₄) andevaporate the solvent in vacuo to give the title compound (29.9 g).

¹H NMR (300 MHz, CDCl₃) δ 1.00, 1.19 (2H each, m), 1.34 (6H, s), 1.95(3H, s), 2.65 (1H, m), 4.13 (2H, s), 7.44, 7.95 (2H each, d).

EXAMPLE 39

Step c₁: 2-(4-(4-Chloro-1-oxobutyl)-phenyl-2-methylpropanol

Mix 2-(4-(4-chloro-1-oxo-butyl))-phenyl-2-methyl propanyl acetate,concentrated hydrochloric acid (555 mL), and ethanol (2.5 L) and refluxfor 2.5 hours under a nitrogen atmosphere. Evaporate the solvent invacuo and take the residue up in methylene chloride (1 L). Washsequentially with water (2×400 mL), aqueous potassium carbonate (10%,200 mL) and water (300 mL). Evaporate the solvent in vacuo to give thetitle compound as a light-brown oil (200 g, 90%).

¹H NMR (300 MHz, CDCl₃) δ 1.35 (6H, s), 2.21 (2H, quent.) 3.15, (2H, t),3.64 (2H, s), 3.66 (2H, 5), 7.48, 7.93 (2H each, d).

EXAMPLE 40

Step c₂: 2-(4-(1-Oxo-1-cyclopropanyl))-phenyl-2-methylpropanol

Mix 2-(4-(4-chloro-1-oxobutyl)-phenyl-2-methylpropanol (101 g, 0.34mol), methylene chloride (800 mL), 40% aqueous solution oftetrabutylammonium hydroxide (33 g), and 50% aqueous solution of sodiumhydroxide (162 mL) and reflux for 48 hours. Add water (300 mL), separatethe organic phase and wash with water (2×300 mL). Dry (MgSO₄) andevaporate the solvent in vacuo to give the title compound as alight-brown oil (71.1 g, 96%).

EXAMPLE 41

Step c₃: 2-(4-(1-Oxo-1-cyclopropanyl))-phenyl-2-methylpropanol

Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanyl acetate (4.16g, 14 mmol), ethanol (50 mL) and water (5 mL). Add 50% aqeuous sodiumhydroxide (4.48 mL, 56 mmol). Stir and heat at reflux for 30 minutesthen remove the ethanol in vacuo. Extract the aqueous residue withmethylene chloride (2×25 mL), wash with water (2×25 mL), dry (MgSO₄) andevaporate the solvent in vacuo to give the title compound as a brown oil(2.91 g, 95.3%).

¹NMR (300 MHZ, CDCl₃) δ 1.03, 1.20 (2H each, m), 1.35 (6H, s), 1.70 (1H,t, br), 2.66 (1H, m), 3.64 (2H, d), 7.48, 7.98 (2H each, d).

EXAMPLE 42

Step d₂: 2-(4-(4-Chloro-2-oxo-butyl))-phenyl-2-methylpropionic Acid

Mix powdered potassium permanganate (39.5 g, 0.25 mol), water (34 mL)and acetic acid (200 mL). Stir and cool at 0° C., then add 85%phosphoric acid (4.2 g). Stir vigorously and add2(4-(4-chloro-1-oxo-butyl))-phenyl-2-methylpropanol (24.5 g, 0.1 mol) inacetic acid (50 mL) at such a rate as to keep the temperature below 5°C. Stir for 5.5 hours below 5° C., add ice water (300 mL), then sodiummetabisulfite (45 g) in small portions until the dark brown mixturebecomes colorless. Extract the aqueous solution with methylene chloride(3×50 mL), wash with water (100 mL) then extract with 20% aqueouspotassium carbonate (2×50 mL). Wash the aqeuous phase with methylenechloride (50 mL), cool in an ice-bath and acidify carefully withconcentrated hydrochloric acid until pH 3. Extract with methylenechloride (2×150 mL), wash with water (2×80 mL) and dry (MgSO₄).Evaporate the solvent in vacuo to give the title compound as acrystalline solid (21.25 g).

¹H NMR (300 MHz, CDCl₃) δ 1.63 (6H, s), 2.22 (2H, quent.), 3.17 (2H, t),3.67 (2H, t), 7.50, 7.92 (2H each, d), 12.3 (1H, s, br).

EXAMPLE 43

Step d₅: 2-(4-(1-Oxo-1-cyclopropanyl))-phenyl-2-methylpropionic acid

Method A:

Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol (1.46 g, 6.7mmol), ruthenium chloride (0.036 g, 0.17 mmol), acetonitrile (14 mL),carbon tetrachloride (14 mL) and water (20 mL). Stir vigorously and addsodium periodate (5.85 g) in one portion. Stir at room temperature forone hour longer, partition between methylene chloride (20 mL) and water(5 mL), separate the organic layer, extract the aqeuous layer withmethylene chloride (15 mL) and wash the combined methylene chloridelayers with water (15 mL) and extract with 20% aqueous potassiumcarbonate (2×25 mL). Cool the base solution in an ice-bath, acidifycarefully with concentrated hydrochloride acid to pH 3 and extract intomethylene chloride (2×30 mL). Wash with water (15 mL), dry (MgSO₄) andevaporate the solvent in vacuo to give the title compound as a yellowoil (1.41 g, 90%).

¹H NMR (300 MHz, CDCl₃) δ 1.04, 1.23 (2H each, d), 1.63 (6H, s), 2.65(1H, m), 7.50, 7.99 (2H each, d).

Method B:

Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol (10.9 g, 50mmol), ruthenium chloride (0.032 g, 0.16 mmol), acetic acid (100 ml) andwater (25 mL). Cool to 10° C. and add, by dropwise addition, an aqueoussolution of sodium hypochloride (70 ml), stirring vigorously over a30-minute period. Stir below 10° C. for 30 minutes longer, evaporatemost of the solvent in vacuo and take the residue up in methylenechloride (120 mL). Wash the methylene chloride solution with water (2×40mL) and extract with 20% aqueous potassium carbonate (2×50 mL). Cool thebase solution in an ice-bath, acidify carefully with concentratedhydrochloride acid to ph 3 and extract into methylene chloride (2×50mL). Wash the organic layer with water (40 mL), dry (MgSO₄) andevaporate the solvent in vacuo to give the title compound as alight-yellow oil (5.46 g, 47%).

Method C:

Mix potassium permanganate (3.61 g, 22.8 mmol), water (2 mL) and aceticacid (10 mL). Stir and cool to 10° C. and add 85% phosphoric acid (500mg). Add, by dropwise addition, a solution2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol (1.66 g, 7.6 mmol)in acetic acid (5 mL) over 5 minutes. Stir below 10° C. for 1 hour andthen at room temperature for 5 hours. Add water (20 mL) followed byaddition of Na₂S₂O₅ in small portions until the solution becomescolorless. Extract with methylene chloride (2×50 mL), wash the methylenechloride solution with water (30 mL) and then extract with 10% aqueouspotassium carbonate (2×50 mL). Cool the base solution in an ice-bath,acidify carefully with concentrated hydrochloric acid to pH 3 andextract with methylene chloride (2×50 mL). Wash the organic layer withwater (20 mL), dry (MgSO₄) and evaporate the solvent in vacuo to givethe title compound as a colorless needles (1.20 g, 68%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (4H, d), 1.50 (6H, s), 7.49, 8.00 (2Heach, d), 12.6 (1H, s, br).

Method D:

Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol (2.30 g, 10.6mmol), acetic acid (5.5 mL) and fuming nitric acid (6.5 mL). Stir andheat at 48-50° C. for 2 hours, cool and add ice water (20 mL) followedby methylene chloride (60 mL). Separate the organic layer, wash withwater (2×20 mL) and extract into 10% aqueous potassium carbonate (2×40mL). Wash the alkaline solution with methylene chloride (10 mL) and coolin an ice-bath. Acidify carefully with concentrated hydrochloric acid toph 3, extract with methylene chloride (2×40 mL), wash the combinedorganic layers with water (20 mL), dry (MgSO₄) and evaporate the solventinvacuo to give the title compound as light-yellow needles (1.89 g,77%).

Method E:

Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol (2.26 g, 10.4mmol), sodium nitrite (60 mg), acetic acid (5 mL) and concentratednitric acid (6 mL, d=1.42, 70%, 94 mmol). Stir and heat at 48-50° C. for2 hours, cool and dilute with ice water (20 mL). Extract into methylenechloride (2×30 mL), wash the combined organic layers with water (2×20mL) and extract into 10% aqeuous potassium carbonate (2×40 mL). Wash thealkaline solution with methylene chloride (10 mL) and cool in anice-bath. Acidify carefully with concentrated hydrochloric acid to pH 3and extract into methylene chloride (2×40 mL). Wash the combined organiclayers with water (20 mL), dry (MgSO₄) and evaporate the solvent invacuo to give the title compound as light yellow needels (2.01 g, 83%).

EXAMPLE 44

Step d₆: 2-(4-(1-Oxo-1-cyclopropanyl))-phenyl-2-methylpropionic Acid

Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanyl acetate (5.0g, 0.0197 mol), sodium nitrite (100 mg), acetic acid (10 mL) andconcentrated nitric acid (8.7 mL, d=1.42, 70%, 0.137mol). Stir and heatat 48-50° C. for 5.5 hours, cool and dilute with ice water (40 mL).Extract into methylene chloride (2×70 mL), wash the combined methylenechloride extracts with water (2×50 mL) and reduce the volume to 50 mL invacuo. Extract with 10% aqueous potassium carbonate (2×50 mL), was thebase solution with methylene chloride (20 mL) and cool in an ice-bath.Acidify carefully with concentrated hydrochloric acid to pH 3 andextract into methylene chloride (2×60 mL). Wash the combined methylenechloride extracts with water (30 ml), dry (MgSO₄) and evaporate thesolvent in vacuo to give the title compound as a crystalline solid (4.12g, 90%).

The novel intermediates of formula (X) wherein R₅ is H, Br, Cl, I, CN,—COOH, —COOalkyl or —CONR₆R₇ may be prepared as described in Scheme J.In Scheme J, all substituents are as previously defined unless otherwiseindicated.

Scheme J provides various general synthetic procedures for preparing thenovel intermediates of formula (X) wherein R₅ is H, Br, Cl, I, CN,—COOH, —COOalkyl or —CONR₆R₇.

In step a, the ketone functionality of the appropriateω-halo-halocumylketone compound of structure (10) is reduced to give thecorresponding ω-halo-halocumylalcohol compound of structure (60).

For example, reduction of the appropriate ω-halo-halocumylketonecompound of structure (10), using, for example, a suitable reducingagent such as sodium borohydride, potassium borohydride, sodiumcyanoborohydride, or tetramethylammonium borohydride is carried out inlower alcohol solvents, such as, methanol, ethanol, isopropyl alcohol orn-butanol at temperatures ranging from about 0° C. to the refluxtemperature of the solvent, and the reaction time varies from about ½hour to 8 hours. Other suitable reducing agents are, for example,lithium tri-tert-butylaluminohydride and diisobutylaluminum hydride.These reduction reactions are carried out in suitable solvents diethylether, tetrahydrofuran or dioxane at temperatures ranging from about 0°C. to the reflux temperature of the solvent, and the reaction timevaries from about ½ hour to 8 hours.

Catalytic reduction may also be employed in the preparation ofappropriate ω-halo-halocumylalcohol compound of structure (60) from anappropriate ω-halo-halocumylketone compound of structure (10), usinghydrogen gas in the presence of a suitable catalyst such as Raneynickel, palladium, platinum or rhodium catalysts in lower alcoholsolvents, such as, methanol, ethanol, isopropyl alcohol or n-butanol oracetic acid or their aqueous mixtures, or by the use of aluminumisopropoxide in isopropyl alcohol.

In addition, a chiral reduction of the appropriateω-halo-halocumylketone compound of structure (10), using, for example,(+)-B-chlorodiisopinocamphenylborane gives the corresponding(R)-ω-halo-halocumylalcohol compound of structure (60) and(−)-B-chlorodiisopinocamphenylborane gives the corresponding(S)-ω-halo-halocumylalcohol compound of structure (60). Other suitablechiral reducing agents are, (R) and (S)-oxazaborolidine/BH3, potassium9-O-(1,2:5,6-di-O-isopropylidine-α-D-glucofuransoyl)-9-boratabicyclo[3.3.1]nonane,(R) and (S)-B-3-pinanyl-9-borabicyclo[3.3.1]nonane, NB-Enantride,Lithium (R)-(+) and (S)-(−)-2,2′-dihydroxy-1,1′-binaphthyl alkoxylaluminum hydride, (R)-(+) and(s)-(−)-2,2′-dihydroxy-6,6′-dimethylbiphenyl borane-amine complex,tris[[(1S,2S,5R)-2-isopropyl-5-methyl-cyclohex-1-yl]methyl]aluminum,[[(1R,3R)-2,2-dimethylbicyclo[2.2.1]hept-3-yl]methyl]beryllium chloride,(R)-BINAP-ruthenium complex/H₂ and6,6′-bis(diphenylphosphino)-3,3′-dimethoxy-2,2′,4,4′-tetramethyl-1,1′-biphenyl.

In step b, the ketone functionality of the appropriateω-halo-cyanocumylketone compound of structure (19) is reduced to givethe corresponding ω-halo-cyanocumylalcohol compound of structure (61) asdescribed previously in step a.

In step c, the ketone functionality of the appropriateω-halo-cyanocumylketone compound of structure (8) is reduced to give thecorresponding ω-halo-cyanocumylalcohol compound of structure (62) asdescribed previously in step a.

In step d, the α-halo functionality of the appropriateω-halo-halocumylalcohol compound of structure (60) is cyanated to givethe corresponding ω-halo-cyanocumylalcohol compound of structure (61) asdescribed previously in Scheme D, step a.

In step e, the appropriate ω-halo-cyanocumylalcohol compound ofstructure (62) is cyanated to give the correspondingω-halo-cyanocumylalcohol compound of structure (61) as describedpreviously in Scheme D, step b.

In step f, the appropriate appropriate ω-halo-cyanocumylalcohol compoundof structure (62) is halogenated to give the correspondingω-halo-halocumylalcohol compound of structure (60) as describedpreviously in Scheme B, step a.

In step g, the α-halo functionality of the appropriateω-halo-halocumylalcohol compound of structure (60) is converted to thecorresponding carboxy to give theω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid compound of structure(64) as described previously in Scheme H, step h.

In step h, the nitrile functionality of the appropriateω-halo-cyanocumylalcohol compound of structure (61) is converted to thecorresponding ester to give theω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid ester compound ofstructure (63) as described previously in Scheme H, step a.

In step i, the nitrile functionality of the appropriateω-halo-cyanocumylalcohol compound of structure (61) is converted to thecorresponding acid to give theω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid compound of structure(64) as described previously in Scheme H, step e.

In step j, the nitrile functionality of the appropriateω-halo-cyanocumylalcohol compound of structure (61) is converted to thecorresponding amide to give theω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid amide compound ofstructure (65) wherein R₆ and R₇ are each hydrogen as describedpreviously in Scheme H, step b.

In step k, the ketone functionality of the appropriateω-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound of structure(31) is reduced to give the correspondingω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid ester compound ofstructure (63) as described previously in step a.

In step l, the ketone functionality of the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)is reduced to give the correspondingω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid compound of structure(64) as described previously in step a.

In step m, the ketone functionality of the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid amide compound ofstructure (40) is reduced to give the correspondingω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid amide compound ofstructure (65) as described previously in step a.

In step n, the carboxy ester functionality of the appropriateω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid ester compound ofstructure (63) is hydrolyzed to give the correspondingω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid compound of structure(64) as described previously in Scheme H, step c.

In step o, the carboxy functionality of the appropriateω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid compound of structure(64) may be esterified by techniques and procedures well known andappreciated by one of ordinary skill in the art to give thecorresponding ω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid estercompound of structure (63) as described previously in Scheme H, step d.

In step p, the carboxy functionality of the appropriateω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid compound of structure(65) may be amidated by techniques and procedures well known andappreciated by one of ordinary skill in the art to give thecorresponding ω′-halo-α′-hydroxy-α,αdimethylphenylacetic acid amidecompound of structure (57) as described previously in Scheme H, step g.

In step q, the amide functionality of the appropriateω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid amide compound ofstructure (65) is converted to the corresponding acid by acid hydrolysisas is known in the art to give theω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid compound of structure(64) as described previously in Scheme H, step f.

In addition, the novel intermediates of formula (X) wherein R₅ is —CH₂ODmay be prepared as described in Scheme K. In Scheme K, all substituentsare as previously defined unless otherwise indicated.

In Scheme K, the ketone functionality of the appropriateω′-halo-α′-keto-(2-methylpropanol)benzene compound of structure (60) isreduced to give the correspondingω′-halo-α′-hydroxy-(2-methylpropanol)benzene compound of structure (66)as described previously in Scheme J, step a.

The novel intermediates of formula (XI) wherein R₅ is hydrogen, CN,COOalkyl or CONR₆R₇ may be prepared as described in Scheme L. In SchemeL, all substituents are as previously defined unless otherwiseindicated.

Scheme L provides various general synthetic procedures for preparing thenovel intermediates of formula (XI) wherein R₅ is hydrogen, CN, COOalkylor CONR₆R₇.

In step a, the ω′-halo functionality of the appropriateω-halo-α′-keto-α,α-dimethylphenyl compound of structure (67) wherein R₅is hydrogen, CN, COOalkyl or CONR₆R₇ is alkylated with the appropriatepiperidine compound of structure (68) to give the correspondingω′-piperdine-α′-keto-α,α-dimethylphenyl compound of structure (69)wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇.

For example, the ω′-piperidine-α′-keto-α,α-dimethylphenyl compound ofstructure (69) wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇ may beprepared by reacting the appropriate ω′-halo-α′-keto-α,α-dimethylphenylcompound of structure (67) wherein R₅ is hydrogen, CN, COOalkyl orCONR₆R₇ with the appropriate piperidine compound of structure (68) in asuitable solvent preferably in the present of a suitablenon-nucleophilic base and optionally in the presence of a catalyticamount of an iodide source, such as potassium or sodium iodide. Thereaction time varies from about 4 to 120 hours and the reactiontemperature varies from about 70° C. to the reflux temperature of thesolvent. Suitable solvent for the alkylation reaction include alcoholsolvents such as, methanol, ethanol, isopropyl alcohol, or n-butanol;ketone solvents, such as, cyclohexanone, methyl isobutyl ketone;hydrocarbon solvents, such as, benzene, toluene or xylene; halogenatedhydrocarbons, such as, chlorobenzene or methylene chloride ordimethylformamide. Suitable non-nucleophilic bases for the alkylationreaction include inorganic bases, for example, sodium bicarbonate,potassium carbonate, or potassium bicarbonate or organic bases, such as,a trialkylamine, for example, triethylamine or pyridine, or an excess ofan appropriate piperidine compound of structure (68) may be used.

For those piperidine compounds of structure (68), wherein R₁ is hydroxy,it is Preferred that R₁ be unprotected for utilization in the alkyationreaction of step a, but those hydroxy functionalities present in thepiperidine compounds of structure (68), wherein R₁ is hydroxy may beprotected with a suitable protecting group. The selection andutilization of suitable protecting groups for the piperidine compoundsof structure (68), wherein R, is hydroxy is well known by one ofordinary skill in the art and is described in “Protective Groups inOrganic Syntheses”, Theodora W. Greene, Wiley (1981). For example,suitable protecting groups for those hydroxy functionalities presentinclude ethers such as tetrahydrothiopyranyl, tetrahydrothiofuranyl,2-(phenylselenyl)ethyl ether, o-nitrobenzyl ether, trimethylsilyl ether,isopropyldimethylsilyl ether, t-butyldimethylsilyl ether,t-butyldiphenylsilyl ether, tribenzylsilyl ether, triisopropylsilylether; and esters, such as acetate ester, isobutyrate ester, pivaloateester, adamantoate ester, benzoate ester, 2,4,6-trimethylbenzoate(mesitoate) ester, methyl carbonate) p-nitrophenyl carbonate,p-nitrobenzyl carbonate, S-benzyl thiocarbonate and N-phenylcarbamate.

The piperidine compounds of structure (68) are readily available to oneof ordinary skill in the art and are described in U.S. Pat. No.4,254,129, Mar. 3, 1981, U.S. Pat. No. 4,254,130, Mar. 3, 1981, U.S.Pat. No. 4,285,958, Apr. 25, 1981 and U.S. Pat. No. 4,550,116, Oct. 29,1985. The piperidine compounds of structure (68) wherein R₁ and R₂ forma second bond between the carbon atoms bearing R₁ and R₂ may be preparedby dehydration of the corresponding compound wherein R₁ is hydroxy byprocedures generally known in the art, such as refluxing in stronglyacidic solution.

The piperidine compounds of structure (68) include the limitationsprovided for previously for piperidine derivatives of formula (I) and(XI) in that when R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0.

In step b, the ω′-halo functionality of the appropriateω-halo-α′-hydroxy-α,α-dimethylphenyl compound of structure (70) whereinR₅ is hydrogen, CN, COOalkyl or CONR₆R₇ is alkylated with theappropriate piperidine compound of structure (68) to give thecorresponding ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compound ofstructure (71) wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇ asdescribed previously in step a.

In step c, the ketone functionality of the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl compound of structure (69)wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇ is reduced to give thecorresponding ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compound ofstructure (71) wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇.

For example, reduction of the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl compound of structure (69)wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇, using, for example, asuitable reducing agent such as sodium borohydride, potassiumborohydride, sodium cyanoborohydride, or tetramethylammonium borohydrideis carried out in lower alcohol solvents, such as, methanol, ethanol,isopropyl alcohol or n-butanol at temperatures ranging from about 0° C.to the reflux temperature of the solvent, and the reaction time variesfrom about ½ hour to 8 hours. Other suitable reducing agents are, forexample, lithium tri-tert-butylaluminohydride and diisobutylaluminumhydride. These reduction reactions are carried out in suitable solventsdiethyl ether, tetrahydrofuran or dioxane at temperatures ranging fromabout 0° C. to the reflux temperature of the solvent, and the reactiontime varies from about ½ hour to 8 hours.

Catalytic reduction may also be employed in the preparation ofappropriate ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compound ofstructure (71) wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇ from anappropriate ω′-piperidine-α′-keto-α,α-dimethylphenyl compound ofstructure (69) wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇, usinghydrogen gas in the presence of a suitable catalyst such as Raneynickel, palladium, platinum or rhodium catalysts in lower alcoholsolvents, such as, methanol, ethanol, isopropyl alcohol or n-butanol oracetic acid or their aqueous mixtures, or by the use of aluminumisopropoxide in isopropyl alcohol.

Reduction using sodium borohydride or potassium borohydride is preferredover catalytic reduction for thoseω′-piperidine-α′-keto-α,α-dimethylphenyl compound of structure (69)wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇ and wherein R₁ and R₂taken together form a second bond between the carbon atoms bearing R₁and R₂.

In addition, a chiral reduction of the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl compound of structure (69)wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇, using, for example,(+)-B-chlorodiisopinocamphenylborane gives the corresponding(R)-ω′-piperidine-α′-keto-α,α-dimethylphenyl compound of structure (69)wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇ and(−)-B-chlorodiisopinocamphenylborane gives the corresponding(S)-ω′-piperidine-α′-keto-α,α-dimethylphenyl compound of structure (69)wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇. Other suitable chiralreducing agents are, (R) and (S)-oxazaborolidine/BH₃, potassium9-O-(1,2:5,6-di-O-isopropylidine-α-D-glucofuransoyl)-9-boratabicyclo[3.3.1]nonane,(R) and (S)-B-3-pinanyl-9-borabicyclo[3.3.1]nonane, NB-Enantride,Lithium (R)-(+) and (S)-(−)-2,2′-dihydroxy-1,1′-binaphthyl alkoxylaluminum hydride, (R)-(+) and(S)-(−)-2,2′-dihydroxy-6,6′-dimethylbiphenyl borane-amine complex,tris[[(1S,2S,5R)-2-isopropyl-5-methyl-cyclohex-1-yl]methyl]aluminum,[[(1R,3R)-2,2-dimethylbicyclo[2.2.1]hept-3-yl]methyl]beryllium chloride,(R)-BINAP-ruthenium complex/E₂ and6,6′-bis(diphenylphosphino)-3,3′-dimethoxy-2,2′,4,4′-tetramethyl-1,1′-biphenyl.

Starting materials for use in Scheme L are readily available to one ofordinary skill in the art.

The following examples present typical syntheses as described in SchemeK. These examples are understood to be illustrative only and are notintended to limit the scope of the present invention in any way. As usedherein, the following terms have the indicated meanings: “g” refers tograms; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “C” refers to degrees Celsius; “mm Eg” refersto millimeters of mercury; “μL” refers to microliters; “μg” refers tomicrograms; and “μM” refers to micromolar.

EXAMPLE 45

Step a:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticAcid Methyl Ester

Mix methyl 4′-(4-chloro-1-oxobutyl)-α,α-dimethylbenzene acetate (0.335mol),α,α-diphenyl-4-piperidinemethanol (101.8 g, 0.335 mol), potassiumhydrogen carbonate (83.8 g, 0.838 mol), potassium iodide (1.00 g, 0.006mol), toluene (600 mL) and water (220 mL). Stir at reflux for 72 hours,add toluene (200 mL) and deionized water (100 mL). Filter through filteraid while at 80° C. and separate the organic phase. Dry (MgSO₄), filterand purify by chromatography to give the title compound.

EXAMPLE 46

Step a:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticAcid Ethyl Ester

Method A:

Remove the still head from the reaction flask containing a solution ofethyl 4′-(4-chloro-1-oxobutyl)-α,α-dimethylbenzene acetate and xylenesobtained from Example 11, Method G and reattach a reflux condenser. Atambient temperature, add azacyclonol free base which has beenrecrystallized from toluene (178.28 g, 0.660 mol) and stir at 175 RPMwhile heating by heating mantle. After the temperature of the reactionslurry reaches 137 (approximately 30 minutes), stir the reaction for 5.5hours, maintaining the temperature betwwen 137-144 C. Remove the heatingmantle, add mixed xylenes (100 mL) and allow the reaction slurry to coolto 64 C. Increase the stirring rate to 300 RPM and add glacial aceticacid (15.17 g, 0.253 mol). Maintain the temperature at 64-69 C for 1.9hours by heating with mantle, cool from 64-60 C over a period of 15minutes; and from 60-50 C over a period of 32 minutes; from 50-42 C overa period of 33 minutes. Filter at 42 C by suction through a 350 mLcoarse sintered glass filter funnel and wash the filtercake with mixedxylenes (200 mL) at ambient temperature. Allow the filtrate to stand atambient-temperature overnight then place in a 1 L flask. Add isopropanol(40 mL) and attached an overhead paddle stirrer. With stirring at 150RPM, slowly add 37% aqeuous concentrated HCl at ambient temperature,adding 2.00 g during the first 17 minutes, adding a total of 33.13 g ofHCl over 245 minutes. After the slurry has been digested, collect thesolids by suction filtration through a 350 mL coarse sintered glassfunnel and wash the filtercake with fresh xylenes (200 mL) and then withn-heptane (100 mL). Dry the filtercake under vacuum at 47 C for 2.5 daysto give the title compound as an off-white solid (141.17 g, 81%).

Concentrate the filtrate by rotary evaporator to give a thick residue ofsolids and syrup (23.78 g) Add acetone (68 g) and agitate by swirlinguntil the syrup dissolves or releases as a solid. Collect the solids bysuction filtration through a medium sintered glass funnel, wash withfresh acetone (17 g) and dry under vacuum to give the title compound asa light tan solid (3.75 g).

Method B:

Place the solution of ethyl 4′-(4-chloro-1-oxobutyl)-α,α-dimethylbenzeneacetate and xylenes obtained from Example 11, Method G in a 1 L, 3-neckround bottom flask and add azacyclonol free base recrystallized fromtoluene (192.2 g, 0.719 mol). Stir the resulting slurry by overheadstirrer and heat to 140 C for 5.5 hours. Allow to cool to ambienttemperature and add a mixture of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid ethyl ester hydrochloride (33.8 g, 0.0318 mol) and azacyclonolhydrochloride (0.0534mol), slurried in mixed xylenes (100 mL). Reheatthe resulting slurry to 135 C with stirring and then allow to coolslowly to ambient temperature.

Vacuum filter and wash the filtercake with xylenes. Dry the filtercakeunder vacuum to give a solid (122.4 g). Concentrate the filtrate byrotary evaporator to a weight of 486 g and add, by dropwise addition, 91g (2.75 g, 0.0753 mol) of a solution of HCl gas (5.6 g) in absolute 2Bethanol (180 mL) at 70-80 C over a 1.5 hour period. Cool slowly to 30 Cand filter by vacuum. Wash the filtercake with mixed xylenes and dryunder vacuum at 50 C to give the title compound as a solid (49.1 g).

To the filtrate from the second filtercake, add absolute 2B ethanol (100mL), heat to 50 C and sparge gaseous HCl (about 5 g) into the solution.Add additional mixed xylenes (170 mL) and absolute 2B ethanol (100 mL)and heat to 70 C. Sparge in additional HCl gas until the total HCl addedis 10 g (0.274 mol). Cool to 50 C and stir for 2 hours then cool toambient temperature and stir overnight.

Distill a total of 240 mL of ethanol and xylenes from the slurry underreduced pressure (80 mm, with pot temperature from 50 to 70 C). Cool to30 C over a 1 hour period and filter by vacuum. Wash the filtercake withtoluene and dry under vacuum at 50 C to give the title compound as asolid (119.2 g).

Method C:

Place ethyl 4′-(4-chloro-1-oxobutyl)-α,α-dimethylbenzene acetate (15.00g, 49.53 mmol), azacyclonol free base (29.66 g, 49.53 mmol) and mixedxylenes (60 mL) in a 250 mL 1-neck round bottom flask fitted with amagentic stir bar and reflux condenser. Heat the reaction mixture toreflux over a period of 15 minutes and then continue at reflux for 5.5hours. Cool to ambient temperature and then to ice/water bathtemperature. Separate the solids from the orange xylenes solution bysuction filtration through a coarse sintered glass funnel, wash thefiltercake with cold xylenes (25 mL) and dry in a vacuum oven at 60 C togive the title compound as an off-white solid (16.21 g).

Method D:

Place azacyclonol free base (35.00 g, 125.68 mmol), ethyl41-(4-chloro-l-oxobutyl)-α,α-dimethylbenzene acetate (17.30 g, 57.13mmol) and mixed xylenes (60 mL) into a 250 mL round bottom flask. Heatto reflux by mantel in 13 minutes and stir by megnetic bar and heat atreflux for 6.3 hours. Remove the heat from the reaction flask and coolby ice/water bath. Filter the cold reaction slurry by suction through acoarse sintered glass funnel and wash the filtercake with fresh mixedxylenes (40 mL). Vacuum dry the filtercake at 40 C overnight to give thetitle compound as a solid (17.87 g).

Add concentrated 37% HCl (2.18 g, 22.1 mmol) to the filtrate, stirred bymagnetic bar. Stir overnight at ambient temperature, filter throughsuction through a coarse sintered glass funnel and wash the filtercakewith fresh mixed xylenes (35 mL) Vacuum dry the filtercake at 50 C togive the title compound as a solid (8.23 g).

Add concentrated 37% HCl (6.42 g, 65.2 mmol) to the filtrate stirred bymagnetic bar. Add mixed xylenes (70 mL) and filter though a coarsesintered glass funnel, at ambient temperature. Wash the filtercake withfresh mixed xylenes (50 mL) and vacuum dry the filtercake to give thetitle compound as a solid (27.25 g).

Purify by recrystallization as follows: Mix the title compound (15 g),absolute 2B ethanol (45 mL) and n-heptane (90 mL) in a 500 mL roundbottom flask with a magentic stir bar. Heat at reflux with stirring for30 minutes, cool by ice/water bath and collect the solids by suctionfiltration through a coarse sintered glass funnel. Wash the filtercakewith 3:1 n-heptane/ethanol (24 mL) and dry under vacuum at 55 C to givethe title compound as a white solid.

EXAMPLE 47

Step c:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticAcid

Add sodium borohydride (0.105 g, 2.77 mmol) to a solution of sodiumhydroxide (0.053 g, 1.33 mmol) in deionized water (2 mL) and add, bydropwise addition, to a solution of4-[4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-1-oxobutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (0.70 g, 1.31 mmol) in ethanol (30 mL). Stir at roomtemperature for 3.5 hours at pH 7-8. Evaporate the solvent in vacuo andstir the residue with methylene chloride (15 mL) and deionized water (15mL). Dry (MgSO₄), acidify to pH 3 with gaseous hydrogen chloride andevaporate the solvent. Add ether with stirring, filter the white solidand wash with additional ether. Dry to give the title compound.

EXAMPLE 48

Step c:(R)-4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic,Ethyl Ester

Dissolve (+)-B-chlorodiisopinocamphenylborane (2.5 g, 7.8 mmol) inanhydrous tetrahydrofuran (5 mL). Add a solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic,ethyl ester (2 g, 3.54 mmol) in anhydrous tetrahydrofuran (5 mL). Stirat room temperature for 3 days and cool to 0° C. Add water (1 mL) and30% hydrogen peroxide (2 mL) and stir for 20 minutes. Add methylenechloride (30 mL),and wash with brine (30 mL), then aqueous sodiumhydrogen carbonate (30 mL), then brine (30 mL). Dry (MgSO₄), evaporatethe solvent in vacuo and purify by chromatography to give the titlecompound.

EXAMPLE 49

Step c:(S)-4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticAcid, Ethyl Ester

Dissolve (−)-B-chlorodiisopinocamphenylborane (2.5 g, 7.8 mmol) inanhydrous tetrahydrofuran (5 mL). Add a solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid, methyl ester (3.54 mmol) in anhydrous tetrahydrofuran (5 mL). Stirat room temperature for 3 days and cool to 0° C. Add water (1 mL) and30% hydrogen peroxide (2 mL) and stir for 20 minutes. Add methylenechloride (30 mL) and wash with brine (30 mL), then aqueous sodiumhydrogen carbonate (30 mL), then brine (30 mL). Dry (MgSO₄), evaporatethe solvent in vacuo and purify by chromatography to give the titlecompound.

EXAMPLE 50

Step a:N,N-Dimethyl-2-(4-{4-[4-hydroxy-diphenylmethyl)-piperidin-1-yl]-butyryl}-phenyl)-isobutyramide

Dissolve N,N-dimethyl-2-[4-(4-chlorobutyryl)-phenyl]-isobutyramide (1.00g, 3.38 mmol) in xylene (3 mL) and add α,α-diphenyl-4-piperidinemethanol(1.09 g, 4.07 mmol) and potassium hydrogen carbonate (0.68 g, 6.76 mmol)in water (2.5 mL). Beat at 100° C. for 20 hours, remove hot water bypipette, dilute with ethyl acetate (20 mL) and wash with water (20 mL).Cool the organic layer to room temperature, dry (MgSO₄), evaporate thesolvent in vacuo and purify by silica gel chromatography (9:1 ethylacetate/methanol) and recrystallize (ethyl acetate/hexane) to give thetitle compound (1.13 g, 63%) as a crystalline solid; mp 135-137° C.

EXAMPLE 51

Step c:N,N-Dimethyl-2-(4-{1-hydroxy-4-[4-hydroxy-diphenlmethyl)-piperidin-1-yl]-butyr}-phenyl)-isobutyramide

DissolveN,N-dimethyl-2-(4-{4-[4-hydroxy-diphenylmethyl)-piperidin-1-yl]-butyryl}-phenyl)-isobutyramide(3.00 g, 5.69 mmol) in ethanol (30 mL), cool using an ice/water bath andadd sodium borohydride (0.87 g, 23.04 mmol) in tetrahydrofuran (10 mL).Remove the cold bath and stir at room temperature for 2.5 hours. Addwater (25 mL) and ethyl acetate (25 mL) and separate the layers. Extractthe aqueous layer with ethyl acetate (20 mL), dry (MgSO₄) and evaporatethe solvent in vacuo to give the title compound (3.06 g, 100%) as awhite foam; mp 166-169° C.

MS (CI, CH₄) m/e 529 (M⁺+1), 28.0, 183.

Anal. Calcd for C₃₄H₄₄N₂O₃.0.3H₂O: C, 77.24; H, 8.39; N, 5.30; Found: C,76.99; H, 8.36; N. 5.17.

EXAMPLE 52

Step a:N-Methoxy-N-methyl-2-(4-{4-[4-hydroxy-diphenylmethyl)-piperidin-1-yl]-butyryl}-phenyl)-isobutyramide

Dissolve N-methoxy-N-methyl-2-[4-(4-chlorobutyryl)-phenyl]-isobutyramide(1.44 g, 4.62 mmol) in 2:1 xylene/water (5 mL) and addα,α-diphenyl-4-piperidinemethanol (1.36 g, 5.07 mmol) and potassiumhydrogen carbonate (0.93 g, 9.24 mmol). Heat at 108° C. for 22 hours,remove hot water by pipette, cool to room temperature and stir for 2days. Evaporate the solvent in vacuo and purify by silica gelchromatography (10:1 ethyl acetate/methanol) and recrystallize (ethylacetate) to give the title compound (1.77 g, 71%) as a white crystallinesolid; mp 159-160.5° C.

MS (CI, CH₄) m/e 543 (M⁺+1), 293, 250, 183.

Anal. Calcd for C₃₄H₄₂N₂O₄.0.3H₂O: C, 74.50; H, 7.83; N, 5.11; Found: C,74.75; H, 7.96; N. 5.15.

EXAMPLE 53

Step c:N-Methoxy-N-methyl-2-(4-{1-hydroxy-4-[4-hydroxy-diphenylmethyl)-piperidine-1-yl]-butyryl}-phenyl)-isobutyramide

DissolveN-methoxy-N-methyl-2-(4-{4-[4-hydroxy-diphenylmethyl)-piperidin-1-yl]-butyryl}-phenyl)-isobutyramide(8.83 g, 16.27 mmol) in 3.5:1 methanol/tetrahydrofuran (85 mL). Addsodium borohydride (0.62 g, 16.27 mmol) in 8 portions over 20 minutes atroom temperature. Stir at room temperature for 2 hours, evaporate thesolvent in vacuo, dissolve the residue in ethyl acetate (60 mL) and addwater (25 m). Stir at room temperature for 10 minutes, separate thelayers and wash the organic layer with brine (2×25 mL). Combine theorganic layers, extract with ethyl acetate (35 mL), dry (Na₂SO₄),evaporate the solvent in vacuo and dry to give the title compound (8.89g, 100%) as a foam; mp 80-83° C.

MS (CI, CH₄) m/e 545 (M⁺+1), 280, 236, 183.

Anal. Calcd for C₃₄H₄₄N₂O₄.0.2H₂O: C, 74.47; H, 8.16; N, 5.12; Found: C,74.08; H, 8.16; N. 4.93.

EXAMPLE 54

Step a:1-[4-(1,1-Dimethyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-phenyl]-4-[4-hydroxy-diphenylmethyl)-piperidine-1-yl]-butan-1-one

Dissolve4-chloro-1-[4-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-phenyl]-butan-1-one(6.88 g, 21.38 mmol) in xylene (14 mL) and add a suspension ofα,α-diphenyl-4-piperidinemethanol hydrochloride (6.50 g, 23.51 mmol) andpotassium carbonate (6.14 g, 4.44 mmol) in water (30 mL). Heat at 100°C. for 24 hours, cool to room temperature, add methylene chloride (100mL) and separate the layers. Extract the aqueous layer with methylenechloride (100 mL), wash with water (150 mL), dry (Na₂SO₄), evaporate thesolvent in vacuo and purify by silica gel chromatography (4:1 ethylacetate/methanol) to give the title compound (8.20 g, 70%) as anoff-white solid.

Anal. Calcd for C₃₆H₄₄N₂O₃.2H₂O: C, 77.72; H, 8.04; N, 5.08; Found: C,77.38; H, 7.91; N, 4.93.

Example 55

Step c:2-(4-{1-Hydroxy-4-[4-hydroxydiphenylmethyl)-piperidin-1-yl]-butyl}-phenyl-)-2-methyl-1-pyrrolidin-1-yl-propan-1-one

Dissolve1-[4-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-phenyl]-4-[4-hydroxy-diphenylmethyl)-piperidine-1-yl]-butan-1-one(0.55 g, 1.00 mmol) in methanol (10 mL) and add sodium borohydride (38mg, 1.00 mmol) at 10° C. Stir at room temperature for 2 hours, evaporatethe solvent in vacuo and dissolve the residue in methylene chloride (60mL). Add water (10 mL) and stir for 10 minutes. Separate the layers,wash with brine (5 mL), dry (Na₂SO₄) and evaporate the solvent in vacuoto give the title compound (0.53 g, 96%) as a white foam; mp 87-93° C.

EXAMPLE 56

Step a:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticAcid, Ethyl Ester Hydrochloride

Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid, ethylester (15.0 g, 49.53 mmol) and α,α-diphenyl-4-piperidinemethanol (29.66g, 106.4 mmol) in xylene (60 mL). Reflux for 5.5 hours, cool in an icebath, filter and wash with cold xylenes (25 mL). Filter the filtratethough silica gel (20 g) and wash the gel with xylenes (40 mL). Addxylene (60 mL) and concentrated hydrochloric acid (6.45 g, 65.6 mmol)with stirring. Add additional xylenes (40 mL) and stir for 2 hour.Filter, wash with xylene (50 mL), vacuum dry and slurry with a mixtureof ethanol (60 mL) and hexane (120 mL) at 70-72° C. for 30 minutes.Filter, wash with 3:1 v/v solution of n-heptane/ethanol (30 mL) and dryto give the title compound as a light white solid (19.7 g, 70%); mp206-208° C.

¹H NMR (300 MHz, CDCl₃) δ 7.90 (d, J=8.7 Hz, 2H), 7.47 (m, 4H), 7.41 (d,J=8.7 Hz, 2H), 7.27 (m, 4H), 7.15 (m, 4H), 4.10 (q, J=7.1 Hz, 2H), 2.93(m, 4H), 2.37 (m, 3H), 2.2 (broad s, 1H), 1.92 (m, 4H), 1.59 (s, 6H),1.39 (m, 4H), 1.16 (t, J=7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 199.5,176.1, 149.8, 146.0, 135.5, 128.2, 128.1, 126.4, 125.9, 125.7, 79.4,61.0, 57.8, 53.9, 46.7, 44.1, 36.3, 26.3, 26.2, 21.9, 14.0; IR (CDCl₃)3514, 2945, 1726, 1682, 1446, 1254, 1147 1097 cm⁻¹;

Anal. Calcd for C₃₄H₄₁O₄NeHCl: C, 72.39; H, 7.50; N, 2.48; Found: C,71.68; H, 7.52; N, 2.34.

EXAMPLE 57

Step a:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticAcid, Methyl Ester Hydrochloride

Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid, methylester (2.82 g, 10.0 mmol) and α,α-diphenyl-4-piperidinemethanol (5.58 g,21.0 mmol) in toluene (20 mL). Reflux for 29 hours, cool in an ice bath,filter, filter the filtrate though silica gel (5 g) and wash the gelwith toluene (10 mL). Evaporate the solvent in vacuo and dissolve theresidue in ethyl ether (100 mL). Add anhydrous hydrogen chloride andfilter to give the title compound as an off-white powder (4.2 g, 76%);mp 165-175° C.

¹H NMR (300 MHz, CDCl₃) δ 7.93 (d, J=8.3 Hz, 2H), 7.47 (m, 4H), 7.42 (d,J=8.3 Hz, 2H), 7.30 (m, 4H), 7.18 (m, 2H), 3.64 (s, 3E), 2.96 (m, 4H),2.42 (m, 4H), 1.96 (m, 4H), 1.62 (s, 6H), 1.41 (m, 4H); ¹³C NMR (75 MHz,CDCl₃) δ 199.1, 176.3, 149.4, 145.8, 135.5, 128.1, ,28.0, 127.7, 126.3,125.7, 1225.6, 79.4, 57.9, 54.0, 52.4, 46.9, 44.1, 36.4, 26.4, 26.3, 22;MS (CI/NH₃) 514 (100 (M+H)), 293 (4), 268 (7).

Anal. Calcd for C₃₃H₃₉O₄N.HCl: C, 72.05; H, 7.33; N, 2.55; Found; C,71.85; H, 7.23, N, 2.33.

EXAMPLE 58

Step c:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticAcid, Methyl Ester Hydrochloride

Dissolve4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid, methyl ester hydrochloride (550 mg, 1.00 mmol) in methanol (5 mL)and add sodium borohydride (62.8 mg) in three batches. Stir for 1 hour,add 50% aqueous sodium hydroxide (800 mg) and heat to reflux withstirring. After 3 hours, cool to −10° C., add approximately 1.5 mL of 6NHCl over 10 minutes, filter the solid and wash with ice water (12 mL)such that the final filtrate is pH=5. Dry the resulting solid in vacuo(50-60° C., 10-1 mm) overnight to give the title compound (515 mg, 94%);mp 165-180° C.

¹H NMR (300 MHz, 5% MeOD₄ in CDCl₃) δ 7.50 (d, J=7.3 Hz, 4H), 7.30 (m,8H), 7.18 (t, J=7.0 Hz, 2H), 4.66 (t, J=5.3 Hz, 1H), 3.47 (m, 6H), 2.97(m, 2H), 2.69 (m, 3H), 1.6-2.2 (m, 6H), 1.55 (s, 6H); ¹³C NMR (75 MHz,5% MeOD₄ in CDCl₃) δ 179.1, 145.3, 143.8, 142.3, 128.2, 126.6, 125.7,125.5, 125.4, 78.4 (bis benzylic), 72.5 (benzylic), 57.4, 53.2, 46.2,24.2, 35.9, 26.6, 24.1, 20.8: MS (CI/NH₃) 502 (100 (M+H)), 280 (5), 200(10).

EXAMPLE 59

Step c:2-(4-(1-Hydroxy-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-butyl)-phenyl)-2-methyl-propanol

Dissolve2-(4-(1-oxo-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-butyl)-phenyl)-2-methylpropanolin methanol (450 mL) and stir for 15 minutes at room temperature. Add,-by dropwise addition, a solution of sodium borohydride (2.25 g, 0.06mol) in water (10 mL) over 15 minutes. Stir for another 30 minutes andcool in an ice-bath. Slowly add concentrated hydrochloric acid (4 mL)and water (8 mL) and stir for an additional 20 minutes. Evaporate thesolvent in vacuo and partition the residue between methylene chloride(150 mL) and water (70 mL). Separate the organic phase and extract theaqueous phase with methylene chloride (25 mL). Wash the combined organiclayers with water (2×50 mL), evaporate the solvent in vacuo andrecrystallize (acetone) to give the title compound as white needles(9.53 g, 79%).

1H NMR (300 MHz, DMSO-d₆) δ 7.50 (4H, m), 7.23 (8H, m), 7.12 (2H, m),5.34 (1H, s, br), 4.65 (1H, t), 4.45 (1H, s), 3.38 (2H, t), 2.60 (2H,m), 2.44 (2H, m), 2.20 (2H, t), 1.62 (2H, t), 1.50 (6H, m), 1.98 (6H,s); ¹³C NMR (DMSO-d₆) δ 147.2, 146.0, 143.4, 127.6, 125.6, 125.5, 125.2,78.4, 72.0, 70.9, 58.0, 53.6, 53.5, 43.6, 38.0, 30.5, 25.9, 25.5, 23.1.

Alternatively, the novel intermediates of formula (XI) may be preparedas described in Scheme M. In Scheme M, all substituents are aspreviously defined unless otherwise indicated.

Scheme M provides various alternative general synthetic procedures forpreparing the novel intermediates of formula (XI).

In step a, the appropriate ω′-piperidine-2-methylethylphenyl compound ofstructure (72) is cyanated to give the correspondingω′-piperidine-α,α-dimethylphenylacetonitrile compound of structure (73)as described previously in Scheme D, step b.

In step b, the appropriate ω′-piperidine-2-methylethylphenyl compound ofstructure (72) is halogenated to give the correspondingω′-piperidine-α,α-dimethylbenzyl halide compound of structure (74) asdescribed previously in Scheme B, step a.

In step c, the nitrile functionality of the appropriateω′-piperidine-α,α-dimethylphenylacetonitrile compound of structure (73)is converted to the corresponding ester to give theω′-piperidine-α,α-dimethylphenylacetic acid ester compound of structure(75) as described previously in Scheme H, step a.

In step d, the halo functionality of the appropriateω′-piperidine-α,α-dimethylbenzyl halide compound of structure (74) isconverted to the corresponding carboxy to give theω′-piperidine-α,α-dimethylphenylacetic acid compound of structure (76)as described previously in Scheme H, step h.

In step e, the nitrile functionality of the appropriateω′-piperidine-α,α-dimethylphenylacetonitrile compound of structure (73)is converted to the corresponding carboxy to give theω′-piperidine-α,α-dimethylphenylacetic acid compound of structure (76)as described previously in Scheme H, step e.

In step f, the nitrile functionality of the appropriateω′-piperidine-α,α-dimethylphenylacetonitrile compound of structure (73)is converted to the corresponding amide to give theω′-piperidine-α,α-dimethylphenylacetic acid amide compound of structure(77) wherein R₆ and R₇ are each hydrogen as described previously inScheme H, step b.

In step g, the carboxy ester functionality of the appropriateω′-piperidine-α,α-dimethylphenylacetic acid ester compound of structure(75) is hydrolyzed to give the correspondingω′-piperidine-α,α-dimethylphenylacetic acid compound of structure (76)as described previously in Scheme H, step c.

In step h, the carboxy functionality of the appropriateω′-piperidine-α,α-dimethylphenylacetic acid compound of structure (76)may be esterified by techniques and procedures well known andappreciated by one of ordinary skill in the art to give thecorresponding ω′-piperidine-α,α-dimethylphenylacetic acid ester compoundof structure (75) as described previously in Scheme H, step d.

In step i, the carboxy functionality of the appropriateω′-piperidine-α,α-dimethylphenylacetic acid compound of structure (76)may be amidated by techniques and procedures well known and appreciatedby one of ordinary skill in the art to give the correspondingω′-piperidine-α,α-dimethylphenylacetic acid amide compound of structure(77) as described previously in Scheme H, step g.

In step j, the amide functionality of the appropriateω′-piperidine-α,α-dimethylphenylacetic acid amide compound of structure(77) is converted to the corresponding acid by acid hydrolysis as isknown in the art to give the ω′-piperidine-α,α-dimethylphenylacetic acidcompound of structure (76) as described previously in Scheme H, step f.

Starting materials for use in Scheme M are readily available to one ofordinary skill in the art.

The following examples present typical syntheses as described in SchemeM. These examples are understood to be illustrative only and are notintended to limit the scope of the present invention in any way. As usedherein, the following terms have the indicated meanings: “g” refers tograms; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 60

Step g:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticAcid Hydrochloride

Dissolve4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticAcid Methyl Ester (0.131 mol) in methanol (2.5 L) and add 10% sodiumhydroxide (769 mL, 1.92 mol). Stir at reflux for 1.5 hours, cool to 68°C. and evaporate the solvent in vacuo to a residue. Add chloroform (1 L)and stir until the solids are dissolved. Separate the organic phase andextract the aqueous phase with chloroform (3×300 mL). Combine theorganic phases, dry (MgSO₄) and evaporate the solvent in vacuo to give aresidue. Treat the residue with ethereal HCl, filter and dry to give thetitle compound.

EXAMPLE 61

Step j:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticAcid

DissolveN-methoxy-N-methyl-2-(4-{1-hydroxy-4-[4-hydroxy-diphenylmethyl)-piperidine-1-yl]-butyryl}-phenyl)-isobutyramide(8.35 g, 15.33 mmol) in isopropanol (50 mL) and add potassium hydroxide(8.63 g, 153.7 mmol). Heat to reflux for 2 hours, add additionalpotassium hydroxide (4.35 g, 77.5 mmol) and heat at reflux for anadditional 16 hours. Cool to room temperature, treat with concentratedHCl by dropwise addition until pH=3. Dilute with water (100 mL), stirvigorously for 2 hours, add ethyl acetate (30 mL) and stir for 1 hour.Filter to give the title compound (7.15 g, 87%) as an off-white solid.

MS (CI, CH₄) m/e 502 (M⁺+1), 107.

Anal. Calcd for C₃₂H₃₉NO₄.HCl.2.6H₂O: C, 65.70; H, 7.61; N, 2.39; Found:C, 65.25; H, 7.70; N, 2.36.

EXAMPLE 62

Step j:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticAcid

DissolveN,N-dimethyl-2-(4-{1-hydroxy-4-[4-hydroxy-diphenylmethyl)-piperidin-1-yl]-butyry}-phenyl)-isobutyramide(15.33 mmol) in isopropanol (50 mL) and add potassium hydroxide (8.63 g,153.7 mmol). Heat to reflux for 2 hours, add additional potassiumhydroxide (4.35 g, 77.5 mmol) and heat at reflux for an additional 16hours. Cool to room temperature, treat with concentrated HCl by dropwiseaddition until pH=3. Dilute with water (100 mL), stir vigorously for 2hours, add ethyl acetate (30 mL) and stir for 1 hour. Filter to give thetitle compound (41%).

As one skilled in the art would appreciate, the compounds depicted inSchemes A through M which bear hydroxy or phenolic functionalities maybe protected prior to use in the synthesis depicted in Schemes A throughM using suitable protecting groups. For example, suitable protectinggroups for the phenolic hydroxy include methyl ether,2-methoxyethoxymethyl ether (MEM), cyclohexyl ether, o-nitrobenzylether, 9-anthryl ether, t-butyldimethylsilyl ether, acetate, benzoate,methyl carbamate, benzyl carbamate, aryl pivaloate and arylmethanesulfonate.

As one skilled in the art would appreciate, the compounds depicted inSchemes A through M which bear α-ketone functionalities may be protectedprior to use in the synthesis depicted in Schemes A through M usingsuitable protecting groups. The selection and utilization of suitableprotecting groups for ketone groups is well known by one of ordinaryskill in the art and is described in “Protective Groups in OrganicSyntheses”, Theodora W. Greene, Wiley (1981). For example, suitableprotecting groups for ketone functionalities include acyclic acetals andketals such as dimethyl acetal, cyclic acetals and ketals such as1,3-dioxanes and 1,3-dioxolanes, dithio acetals and ketals such as1,3-dithiane and 1,3-dithiolane, hemithio acetals and ketals,O-substituted cyanohydrins, substituted hydrozones, imines,oxazolidines, imidazolidines and thiazolidines.

As one skilled in the art would appreciate, the compounds depicted inSchemes A through M which bear protected hydroxy and/or ketonefunctionalities may be reacting with appropriate deprotecting agentsprior to use in any of the steps depicted in Schemes A through M. Theselection and utilization of appropriate deprotecting reagents is wellknown by one of ordinary skill in the art and is described in“Protective Groups in Organic Syntheses”, Theodora W. Greene, Wiley(1981). Examples of appropriate deprotecting reagents are mineral acids,strong organic acids, Lewis acids, aqueous mineral bases, catalytichydrogenation and the like.

For example, cleavage of B-methoxyethoxymethyl (MEM) protecting groupson any of the compounds depicted in Schemes A through M which bearprotected hydroxy ketone functionalities, for example, can be achievedby using trifluoroacetic acid at room temperature or using 5 to 8equivalents of powdered anhydrous zinc bromide in methylene chloride atabout 25° C. by the general procedure of E. J. Corey et al., TetrahedronLetters, 11, 809-812 1976.

In addition, the individual (R) and (S) isomers of theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compounds of structure (71)can be prepared by techniques are procedures well known and appreciatedby one of ordinary skill in the art.

For example, the mixture of (R) and (S) isomers of theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compounds of structure (71)may be subjected to chiral chromatography to give the correspondingindividual (R)-ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compounds ofstructure (71) and (S)-ω′-piperidine-α′-hydroxy-α,α-dimethylphenylcompounds of structure (71).

In addition, the individual (R) and (S) isomers of theω-halo-α′-hydroxy-α,α-dimethylphenyl compound of structure (70) and theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compounds of structure (71)can be prepared by techniques and procedures well known and appreciatedby one of ordinary skill in the art and described in “Enanatiomers,Racemates, and Resolutions”, Jacques, Collet and Wilen, Wiley (1981).

One such method involves reacting the mixture of (R) and (S) isomers ofthe ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compounds of structure(71) with appropriate chiral acids to give the corresponding mixture ofdiastereomeric acid addition salts. The individual(R)-ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl chiral acid additionsalt compounds of structure (71) and(S)-ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl chiral acid additionsalt compounds of structure (71) are obtained by recrystallization andthe individual ω′-piperidine-(R)-α′-hydroxy-α,α-dimethylphenyl compoundsof structure (71) and ω′-piperidine-(S)-α′-hydroxy-α,α-dimethylphenylcompounds of structure (71) are obtained by subjecting the individualω′-piperidine-(R)-α′-hydroxy-α,α-dimethylphenyl chiral acid additionsalt compounds of structure (71) andω′-piperidine-(S)-α′-hydroxy-α,α-dimethylphenyl chiral acid additionsalt compounds of structure (71) to base in order to free the piperidinenitrogen from the acid addition complex. Examples of suitable chiralacids are tartaric acid (+), (−), O,O′-dibenzoyltartaric acid (+), (−),O,O′-di-p-toluyltartaric acid (+), (−), 2-Nitrotartranillic acid (+),(−), mandelic acid (+), (−), malic acid (+), (−), 2-phenoxypropionicacid (+), hydratropic acid (+), (−), N-acetylleucine (−), (+),N-(α-methylbenzyl)succinamide (+), -), N-(α-methylbenzyl)phthalamic acid(+), (−), camphor-10-sulfonic acid (+), 3-bromocamphor-9-sulfonic arid(+), (−), camphor-3-sulfonic acid (+), quinic acid (+), (−),Di-O-isopropylidene-2-oxo-L-gulonic acid (−), Lasalocid (−),1,1′-binaphthyl-2,2′-phosphoric acid (+), (−), chloestenonesulfonicacid.

In addition, the individual (R) and (S) isomers of theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compounds of structure (71)can be prepared by reacting the mixture of (R) and (S) isomers of theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compounds of structure (71)with appropriate organic chiral acids to give the corresponding mixtureof diastereomeric acid esters. The individualω′-piperidine-(R)-α′-ester-α,α-dimethylphenyl compounds of structure(71) and ω′-piperidine-(S)-α′-ester-α,α-dimethylphenyl compounds ofstructure (71) are obtained by recrystallization or chromatography andthe individual ω′-piperidine-(R)-α′-hydroxy-α,α-dimethylphenyl compoundsof structure (71) and ω′-piperidine-(S)-α′-hydroxy-α,α-dimethylphenylcompounds of structure (71) are obtained by subjecting the individualω′-piperidine-(R)-α′-ester-α,α-dimethylphenyl compounds of structure(71) and ω′-piperidine-(S)-α′-ester-α,α-dimethylphenyl compounds ofstructure (71) to hydrolysis conditions.

What is claimed is:
 1. A process for preparing a compound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0, comprising the steps of: (a) reacting atoluene compound of the formula

wherein A is as defined above with a ω-halo compound of the formula

wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is asdefined above, in the presence of a suitable Lewis acid to produce aω-halo-tolylketone compound; (b) reacting the ω-halo-tolylketonecompound with a suitable base to give a cyclopropyl-tolylketonecompound; (c) reacting the cyclopropyl-tolylketone compound with asuitable halogenating agent to give a cyclopropyl-halotolylketonecompound; (d) reacting the cyclopropyl-halotolylketone compound with asuitable cyanating agent to give a cyclopropyl cyanotolylketonecompound; (e) reacting the cyclopropyl cyanotolylketone compound with asuitable methylating agent to give a cyclopropyl cyanocumylketonecompound; (f) reacting the cyclopropyl cyanocumylketone compound with asuitable base to give a cyclopropylketo-α,α-dimethylphenylacetic acidamide; (g) converting the cyclopropylketo-α,α-dimethylphenylacetic acidamide into a ω′-halo-α′-keto-α,α-dimethylphenylacetic acid estercompound; (h) reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acidester compound with a piperidine compound of the formula

wherein R₁, R₂ and m are as defined above in the presence of a suitablenon-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative; (i) optionallyhydrolyzing the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative toproduce ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula(I) wherein R₃ is COOH and W is —C(═O)—; (j) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is COOH and W is —CH(OH)—; and (k) optionallyreacting the ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)— with an appropriate straight orbranched C₁-C₆ alcohol in the presence of a suitable acid to produceω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (II)wherein R₃ is —COOalkyl and W is —C(═O)—; and (l) optionally reactingthe ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (II)wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (II)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl of formula (I) wherein R₃ is—COOalkyl and W is —CH(OH)— with an appropriate deprotecting reagent,with the proviso that each of the hydroxy groups present in thecompounds described in steps a-k are optionally protected orunprotected.
 2. A process for preparing a compound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0, comprising the steps of: (a) reacting aphenylacetic acid ester compound of the formula

wherein A is as defined above with a ω-halo compound of the formula

wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is asdefined above, in the presence of a suitable Lewis acid to produceω-halo-α′-keto-phenylacetic acid ester compound; (b) reacting theω-halo-α′-keto-phenylacetic acid ester compound with a suitablemethylating agent in the presence of a suitable base to give acyclopropylketo-α,α-dimethylphenylacetic acid ester; (c) purifying thecyclopropylketo-α,α-dimethylphenylacetic acid ester by distillationand/or recrystallization; (d) converting thecyclopropylketo-α,α-dimethylphenylacetic acid ester into aω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound; (e)reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid estercompound with a piperidine compound of the formula

wherein R₁, R₂ and m are as defined above in the presence of a suitablenon-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; (f) optionally hydrolyzing theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)— to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)—; (g) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)—; and (h) optionallyreacting the ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)— with an appropriate straight orbranched C₁-C₆ alcohol in the presence of a suitable acid to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; and (i) optionally reactingthe ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl of formula (I) wherein R₃ is—COOalkyl and W is —CH(OH)— with an appropriate deprotecting reagent,with the proviso that each of the hydroxy groups present in thecompounds described in steps a-h are optionally protected orunprotected.
 3. A process for preparing a compound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0, comprising the steps of: (a) reacting aphenylacetic acid ester compound of the formula

wherein A is as defined above with a suitable methylating agent to givea α,α-dimethylphenylacetic acid ester; (b) reacting theα,α-dimethylphenylacetic acid ester with a ω-halo compound of theformula

wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is 3, inthe presence of a suitable Lewis acid to produce acyclopropylketo-α-α-dimethylphenylacetic acid ester; (c) purifying thecyclopropylketo-α,α-dimethylphenylacetic acid ester by distillationand/or recrystallization; (d) converting thecyclopropylketo-α,α-dimethylphenylacetic acid ester into aω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound; (e)reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid estercompound with a piperidine compound of the formula

wherein R₁, R₂ and m are as defined above in the presence of a suitablenon-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; (f) optionally hydrolyzing theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)— to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)—; (g) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)—; and (h) optionallyreacting the ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)— with an appropriate straight orbranched C₁-C₆ alcohol in the presence of a suitable acid to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; and (i) optionally reactingthe ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl of formula (I) wherein R₃ is—COOalkyl and W is —CH(OH)— with an appropriate deprotecting reagent,with the proviso that each of the hydroxy groups present in thecompounds described in steps a-h are optionally protected orunprotected.
 4. A process for preparing piperidine derivatives offormula

wherein W represents —C(═O)— or —CH(OH)—; R₃ is —COOH or —COOCH₃; andpharmaceutically acceptable salts and individual optical isomersthereof, comprising the steps of: (a) reacting phenylacetic acid methylester with a suitable methylating ageant in the presence of a suitablebase to give α,α-dimethylphenylacetic acid methyl ester; (b) reactingα,α-dimethylphenylacetic acid methyl ester with a ω-halo compound of theformula

wherein B is halo or hydroxy and Hal represents Cl, Br or I in thepresence of a suitable Lewis acid to produce a mixture of meta and paraisomers of ω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl estercompounds of the formula

wherein Hal is defined above; (c) separating the para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound bycrystallization; (d) reacting the para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound witha piperidine compound of the formula

in the presence of a suitable non-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula

wherein W represents —C(═O); R₃ is —COOCH₃; and pharmaceuticallyacceptable salts and individual optical isomers thereof; (e) optionallyhydrolyzing the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivativewherein R₃ is COOCH₃ and W is —C(═O)— to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula

wherein W represents —C(═O)—; R₃ is —COOH; and pharmaceuticallyacceptable salts and individual optical isomers thereof; (f) optionallyreacting the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative whereinR₃ is COOCH₃ and W is —C(═O)— or theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative wherein R₃ is COOHand W is —C(═O)— with a suitable reducing agent to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative wherein R₃ is—COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative wherein R₃ isCOOCH₃ and W is —CH(OH)—; and (g) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative wherein R₃ is —COOHand W is —C(═O)—, the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative wherein R₃ is —COOCH₃ and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative wherein R₃ is—COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative wherein R₃ is—COOCH₃ and W is —CH(OH)— with an appropriate deprotecting reagent, withthe proviso that the hydroxy groups present in the compounds describedin steps a-f are optionally protected or unprotected.
 5. A processaccording to claim 4 wherein the para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound isfurther separated from the meta isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound byrecrystallization of the para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound. 6.A process according to claim 4 wherein additional para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound isrecovered from the mother liquors of the crystallization step (c),comprising the steps of: (a) reacting the mixture of meta and paraisomers of ω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl estercompounds with a suitable base such as sodium methoxide to give amixture of meta and para isomers of acyclopropyl-α,α-dimethylphenylacetic acid methyl ester of the formula

(b) enriching the para isomer of thecyclopropyl-α,α-dimethylphenylacetic acid methyl ester by removal of themeta isomer of the cyclopropyl-α,α-dimethylphenylacetic acid methylester by distillation; and (c) reacting the enriched para isomer of thecyclopropyl-α,α-dimethylphenylacetic acid methyl ester with a suitableanhydrous acid to give the enriched para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound. 7.A process according to claim 6 wherein the enriched para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound isfurther separated from the meta isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound bycrystallization of the para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound. 8.A process according to claim 7 wherein the para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound isfurther separated from the meta isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound byrecrystallization of the para isomer of theω-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound. 9.The process of claim 1, 2, 3 or 4 wherein R₁ is hydroxy; R₂ is hydrogen;m is zero; n is 3; W is —CH(OH)—; A is hydrogen; and R₃ is —COOH.